Download PML carcinogenesis review

TRECAN 00496 No. of Pages 18
Trends in Cancer
Review
PML Nuclear Body Biogenesis,
Carcinogenesis, and Targeted Therapy
Yuwen Li,1,2 Xiaodan Ma,1,2 Wenyu Wu,1 Zhu Chen,1,* and Guoyu Meng1,*
Targeted therapy has become increasingly important in cancer therapy. For
example, targeting the promyelocytic leukemia PML protein in leukemia has proved
to be an effective treatment. PML is the core component of super-assembled structures called PML nuclear bodies (NBs). Although this nuclear megaDalton complex
was first observed in the 1960s, the mechanism of its assembly remains poorly
understood. We review recent breakthroughs in the PML field ranging from a
revised assembly mechanism to PML-driven genome organization and carcinogenesis. In addition, we highlight that oncogenic oligomerization might also
represent a promising target in the treatment of leukemias and solid tumors.
Highlights
Oligomerization mediated by the conserved RBCC motif is essential for PML
NB assembly. PML NBs are thought to
adopt a phase-separation stage in their
biogenesis pathway.
PML NBs are important regulators of
genome organization.
Oligomerization may also be an important factor in leukemogenesis.
PML and Targeted Therapy
Oligomerization-driven carcinogenesis is
widely observed in solid tumors and
other diseases.
Cancer is the second leading cause of global mortality [1]. Our understanding of the molecular
pathways that underpin the pathogenesis of human cancers has increased dramatically in recent
years. Consequently, this has enabled the design of new targeted therapies (see Glossary),
resulting in markedly improved treatment outcomes. A prime example is acute promyelocytic
leukemia (APL) and PML.
PML NBs play dual roles as tumor
suppressors and oncogenic drivers in
various human cancers.
PML NBs and oncogenic oligomerization are promising targets in cancer
treatment.
The PML gene, which encodes the N-terminal part of the PML–RARα fusion oncoprotein, was
first discovered in an APL patient. It generates several isoforms [2] which can all contribute to
the formation of PML nuclear bodies (NBs) [3], a membraneless super-assembled subnuclear
organelle [4]. The PML protein, the main component of PML NBs, displays remarkable dynamic
activities because it can translocate from the nucleoplasm to PML NBs or between PML NBs in
the nuclear matrix [5]. Numerous reports have shown that PML NBs are involved in numerous
cellular pathways including stem cell self-renewal, transcriptional regulation, DNA damage
responses, cell proliferation, apoptosis, and viral infection defense [6–12].
In APL, the biogenesis of PML NBs is severely disrupted by PML–RARα fusion. The PML–RARα
fusion, which is recognized as a major driver of the disease, is observed in most APL patients
(N95%) [13]. Over the past three decades it has been shown that two compounds, arsenic trioxide (ATO) and all-trans retinoic acid (ATRA), can directly target PML–RARα, resulting in definitive
cure in 95% of APL patients [14–17]. However, the mechanisms concerning disease development and targeted therapy require more in-depth investigation. Recent studies have shown
that oligomerization of PML or PML–RARα is crucial to leukemogenesis and therapy responses
[18,19]. These observations have brought PML biology back into the spotlight. We review here
recent progress in understanding PML NB assembly. In addition, we discuss recent developments in PML-driven genome organization and carcinogenesis, highlighting the idea that
PML NBs and oligomerization might be promising targets in various cancer treatments.
RBCC Oligomerization
PML NBs often appear as 5–30 discrete speckles with diverse sizes and locations attached to
the nuclear matrix [10]. The key component, PML protein, is located at the outer shell of this
Trends in Cancer, Month 2020, Vol. xx, No. xx
1
State Key Laboratory of Medical
Genomics, Shanghai Institute of
Hematology, National Research Center
for Translational Medicine, Rui-Jin
Hospital affiliated to Shanghai Jiao Tong
University School of Medicine,
Shanghai, 200025, China
2
These authors contributed equally
*Correspondence:
[email protected] (Z. Chen) and
[email protected] (G. Meng).
https://doi.org/10.1016/j.trecan.2020.05.005
© 2020 Elsevier Inc. All rights reserved.
1
Trends in Cancer
super-complex [20]. The conserved RBCC in the PML N-terminal region is essential for its polymerization activity and NB formation [18,19]. The tandem arrangement of RING (R), B1/B2 box (B), and
coiled-coil (CC) subdomains is widely observed in the TRIM protein superfamily, in which PML is
identified as TRIM19. It has been reported that numerous TRIMs display E3 ligase activity [21].
RING (really interesting new gene) dimerization appears to enable most TRIM proteins to interact
with ubiquitin E2 ligase [22,23]. TRIM B-box dimerization/trimerization is also important. For
example, B-box trimerization of TRIM5α is thought to be a pivotal turning point for the megaDalton
polymerization that is necessary for virus recognition [24]. The CC motif is often associated with
antiparallel dimerization in most TRIM proteins [25], and similar oligomerization patterns are
observed in PML (also known as TRIM19). Wang and coworkers recently reported the crystal structure of the PML RING tetramer [18]. This is the first observation of a tetrameric organization of a RING
family protein. Disruption of RING tetramerization entirely disrupts NB biogenesis. In addition, the
PML B1-box can contribute to overall PML RBCC oligomerization. The crystal structure of the
B1-box echoes the remarkable polymerization activity of PML [19]. In both cases, oligomerization
is accompanied by new biological function. For example, PML RING tetramerization is thought to
be important for the recruitment of SUMO E2 ligase UBC9 (see later). In the PML B1 network, Nmer like polymerization generates a local concentration of K160, explaining why this position is favored for the poly-SUMOylation modification that is essential for APL leukemogenesis [26]. In line
with the structural observations, Li and coworkers successfully purified RBCC1–256 [19], unveiling
the previously unrecognized dynamic oligomerization of PML. The concerted action by RING, B1/
2-boxes, and CC domains might enable PML dimerization, tetramerization, polymerization, and ultimately 3D assembly into a sphere-like structure (Figure 1).
Phase Separation and Post-translational Modifications in PML NB Formation
Like P granules, stress granules, and Cajal bodies, PML NBs lack a physical barrier to separate internal materials from the external environment [27,28]. PML NBs also appear to be dynamic in cellulo
[3,29,30] because, when expressed in the same cell type, different sizes and quantities are frequently
observed. Furthermore, the positioning of NBs may be dependent on partner proteins concentrated/
recruited into the NB core via SUMO–SIM (SUMO interaction motif) engagement [4,20,31]. It is now
clear that PML can be covalently modified by SUMO-1/SUMO-2/SUMO-3. Thus far, three major
SUMO sites, K65/K160/K490, have been reported [32]. K160, capped by a poly-SUMO-2/3 chain
and terminated by SUMO-1, is distinct from K65 and K490 [33]. The SUMOylation reaction is also
a dynamic process catalyzed by UBC9, various SUMO E3 ligases, and SENP [34,35]. In addition
to SUMO modifications, SIM sequences are often associated with PML itself or its partner proteins.
The SUMO–SIM interaction is an important, but not an essential, factor in PML NB biogenesis
[3,20,36,37]. Furthermore, versatile SUMO–SIM engagements between PML and various partner
proteins (N120) are indicative of remarkable multivalent regulation of PML biogenesis [11,38]. This
is consistent with recent reports that liquid phase condensation might play an important role in the
formation of P granules, Cajal bodies, and nucleoli [39–42]. Such studies suggest that these
membraneless organelles share the same characteristics as liquid-like droplets, leading to the proposal that phase separation might also play a role in PML NB biogenesis. If indeed PML, like
other NB-like structures, adopts a phase-separation stage in its pathway of biogenesis, we suspect
that this process is likely to take place after RBCC oligomerization (Figure 1). The SUMO modifications, which will undoubtedly alter the demixing threshold of the protein, might serve as an important
regulator of PML phase separation, leading to NB formation with various sizes/quantities/positioning
[38]. In addition, SUMO–SIM interactions and partner proteins might allow PML to enter different
phase separations in response to extracellular stresses (Figure 1).
In addition to SUMOylation, other post-translational modifications (PTMs) such as phosphorylation, acetylation, and ubiquitination also occur in PML NBs. PML phosphorylation can
2
Trends in Cancer, Month 2020, Vol. xx, No. xx
Glossary
C-circles: extrachromosomal circular
telomeric DNA composed of a
contiguous C-rich strand and nicked
G-rich complementary strand. C-circles
are a quantitative biomarker of ALT
activity.
Genome organization: the genome
contains chromatin territories,
compartments, and topologically
associated domains that are precisely
packaged inside the nucleus. This
organization plays a crucial role in
mediating cellular biological processes
including DNA replication, transcription,
and cell division.
Interactosome: the networking of a
variety of biomolecules that work
together. This coordination is achieved
mostly by diverse protein–protein
interactions (including SUMO–SIM-like
association) and protein–DNA
interactions.
Oligomerization-driven
carcinogenesis: oligomerization
refers to the process of converting a
monomer or a mixture of monomers
into an oligomer. In the context of
leukemia/solid tumor development,
oncogenic fusions derived from
chromosomal translocations may
enhance intermolecular
oligomerization, leading to
carcinogenesis.
Phase separation: the creation of two
distinct phases from a single
homogeneous mixture, such as oil and
water. Phase separation plays a crucial
role in a variety of cellular processes,
especially in the formation of
membraneless organelles.
PML nuclear bodies (NBs): matrixassociated domains 0.1–2 μm in
diameter in most cell lines and many
tissues. They are proposed to anchor
and regulate many cellular functions.
Post-translational modifications
(PTMs): covalent and enzymatic
modifications of proteins that take place
following protein biosynthesis. PTMs
including SUMOylation,
phosphorylation, acetylation are
catalyzed by a variety of enzymes that
recognize specific target sequences in
specific proteins.
SUMOylation: a classic type of PTM. In
the process of SUMOylation, a small
ubiquitin-related modifier protein
(SUMO) is covalently linked to a lysine
residue in the target protein through the
activities of different ligases (termed E1,
E2, and E3).
Trends in Cancer
Targeted therapy: a potent treatment/
drug that targets the specific genes,
proteins, or tissue environment in cancer
development. Targeted therapy is
recognized as a potent method to fight
cancer, resulting in better overall survival
rate and quality of life.
be catalyzed by kinases such as ATR, CHK2, and CK2 [8,43,44]. In response to DNA damage,
PML is phosphorylated by CHK2 to mediate cell death, and PML-induced apoptosis through
phosphorylation of PML by ATR is proposed to regulate PML subnuclear localization and p53
stability via MDM2 sequestration [8]. Notably, CK2, that is frequently upregulated in multiple
tumors, could directly target PML S517 to promote its ubiquitin-mediated degradation, which
negates its tumor-suppressive properties [44]. PML acetylation at the positions of K487 and
K515, which is catalyzed by P300, is thought to be important in HDAC (histone deacetylase)
inhibitor TSA (trichostatin A)-induced cell apoptosis [45]. Furthermore, PML K487 acetylation
can also be downregulated by H2O2 treatment. Deacetylation of K487 by SIRT1 and SIRT5
might interfere with H2O2-induced cell death [46]. Intriguingly, K487 acetylation is mutually
exclusive with K490 SUMOylation, and this indicates potential interplay between PML PTMs.
Ubiquitination activated by E3 ligases E6AP and RNF4 often results in PML degradation
[47,48]. E6AP-mediated PML ubiquitination and degradation ultimately can prevent senescence
in MYC-induced B cell lymphomagenesis [49]. More importantly, as demonstrated in APL
L73
L73
F52
F52
F52
F52
6. B1 network
F52
n
Partner protein
recruitment
Phase separation
7. RBCC-driven
PML NB assembly
and dynamics
Interplay of PTMs
Trends in Cancer
Figure 1. A Revised Model of Promyelocytic Leukemia Protein (PML) Nuclear Body (NB) Biogenesis. RBCC motif-mediated oligomerization might be the first
step in PML NB biogenesis. In the conserved RBCC motif, RING tetramerization might be primed by F52/54 and L73 interfaces (1, 2, and 3). L73–L73 dimerization might
be the docking site of the sole SUMO E2 UBC9 and allow PML autoSUMOylation in trans (4,5). Subsequent B1 networking might explain how normal TRIM-like
multimerization can turn viral, leading to a remarkable 'shell'-like assembly with diameters of 0.1–2 μm (6). Upon RBCC oligomerization, the partner proteins are
recruited to the core (circled) relying on diverse post-translational modifications (PTMs), especially the SUMO–SIM interactions (7). Based on studies of other nuclear
bodies [39–42], enhanced polymerization driven by a phase-separation process might trigger droplet-like formation, accounting for the variation/dynamic exchange of
NBs that are frequently observed in cells (7).
Trends in Cancer, Month 2020, Vol. xx, No. xx
3
Trends in Cancer
therapy, the poly-SUMO-specific E3 ubiquitin ligase RNF4 can trigger PML degradation in response to ATO [47]. These PTMs can often cooperate with each other. It has been demonstrated
that phosphorylation at S517 can significantly enhance ubiquitination [44]. Many serine residues
(including S505/518/527/530 adjacent to the SIM region) can be phosphorylated, and this may
enhance PML SUMOylation [50]. Similar crosstalk can also be observed between PML acetylation and SUMOylation [46]. PTMs are not restricted to PML. Within PML NBs, PTMs are frequently observed in partner proteins. It has been shown that phosphorylation of SIMs might
increase the number of negatively charged residues flanking the hydrophobic core, thereby facilitating binding to the positively charged residues in SUMOs [51–53]. Conversely, acetylation of
SUMO proteins can also regulate the SUMO–SIM interaction in PML NBs [54]. Proteomic analysis
has confirmed the interplay between SUMOylation, phosphorylation, and ubiquitination. It has
been shown that N800 SUMOylated peptides are comodified by phosphorylation, and dozens
of SUMOylated peptides are comodified by ubiquitylation, acetylation, and methylation [55].
Through these processes PML NBs establish diverse cellular signaling networks via partner proteins and are involved in cell apoptosis/senescence regulation, PML-mediated alternative lengthening of telomeres (ALT), the DNA repair pathway, and transcriptional regulation [10,11]. In the
case of P53-related apoptosis pathways, the partner proteins including P53, CBP, and AXIN
are recruited into PML NBs. CBP can enhance P53 acetylation whereas AXIN contributes to
the phosphorylation of P53 [56–58]. In addition, PML can facilitate P53 phosphorylation via
CHK2 recruitment, which in turn sequesters P53 from MDM2-mediated degradation [59]. Conversely, PML NBs can activate P53 via MDM2 sequestration in the nucleolus [8]. In parallel,
PML might recruit SIRT1 deacetylase to deacetylate P53, resulting in P53 repression [60]. In addition, MDM2 can also be released to fine-tune P53 activity via the activation of MAPK1 [61]. A
recent study also shows that MAD1, which is upregulated in human breast cancer, displaces
MDM2 from PML to ubiquitinated P53, triggering tumorigenesis [62].
PML NBs in Genome Organization
PML NBs and Chromatin Architecture
PML NBs are frequently observed in the interchromatin space in the nucleus [63]. PML NBs are
depots of multiple DNA-related processes including chromosomal activation and nascent
DNA synthesis [29,64]. PML NBs are often recruited to specific chromatin or genomic loci, in
preparation for the regulation of chromatin architecture and DNA metabolic processes
(Figure 2A) [65–67]. PML expression and its dynamic assembly, as characterized by various
NB sizes/counts in the nucleus, are strictly regulated by the status of chromosomal ploidy and
the cell cycle [68,69]. In interphase, PML NBs, which are immobile, appear to maintain their relative positioning through extensive contacts with surrounding chromatin. When the cell cycle proceeds to the S phase, changes in DNA topology caused by DNA replication might compromise
the integrity of the NBs. PML NBs undergo fission from the parental PML nuclear bodies in
early S phase, followed by redistribution and migration with chromatin fibers [69]. In addition,
PML NBs derived from nuclear fission in S phase can also maintain chromosomal domain
order by spatially orienting sister chromatids before prophase. Interestingly, Pml–/– mice display
higher rates of sister chromatid exchange (SCE; a characteristic of Bloom syndrome [70]). Therefore, chromatin topology can influence the integrity and dynamics of PML NBs during mitosis.
Vice versa, PML NBs also play a crucial role in safeguarding genome integrity during DNA
synthesis or in maintaining functional chromosomal domains before mitosis.
PML is Essential for the Deposition of Histone Variant H3.3 on the Genome
Proper delivery of histone variants to the genome is crucial for chromatin homeostasis [71]. H3.3
can be deposited at active sites, telomeres, and pericentric heterochromatin by various
4
Trends in Cancer, Month 2020, Vol. xx, No. xx
Trends in Cancer

Cell cycle
DNA topology

ATRX
DAXX
HIRA
DEK
Chaperones
Deposition of histone
variant H3.3

Regulation of
chromatin architecture
PML NB
H3.3
PML NB
Modulation of DNA
methylation status and
chromatin remodeling
Maintenance of
chromatin homeostasis
Epigenetic regulation
PML NB

DNA damage sensing and DNA repair
MRE11
NBS1
RAD50
CHK2
ATM
ATR


53BP1
BRCA1
BLM
RAD51
PML NB
Genome organization
and stability
APB formation
LLPS
BLM/RAD52
SLX4
BTR
PM
L
Telomere maintenance
APB
MRN, RAD52, TRF1/2, TSPYL5, etc.
Telomeric DNA, PML
Trends in Cancer
Figure 2. Promyelocytic Leukemia Protein (PML) Nuclear Bodies (NBs) Are Involved in Genome Organization.
(A) PML NBs are important factors in safeguarding genomic integrity during DNA synthesis and ensure correct positioning of
functional chromosomal domains before mitosis. (B) PML NBs, together with diverse chaperones ATRX, DAXX, HIRA, and
DEK, are essential for H3.3 deposition and chromatin homeostasis. (C) By modulating the state of DNA methylation and
chromatin remodeling, PML NBs are crucial in epigenetic regulation. (D) PML NBs can orchestrate the recruitment of
various partner proteins in response to DNA damage sensing and repair. (E) Alternative lengthening of telomeres (ALT)associated PML body (APB) formation is required for telomere maintenance. PML, a key component in APB, can
contribute to the localization of the BLM–TOP3A–RMI (BTR) complex to telomere ends, hence promoting ALT activity.
Interplay of BLM/RAD52–PML and SLX4–PML is thought to regulate APB formation and telomere clustering/extension.
chaperones [72,73]. PML NBs play a key regulatory role in H3.3 recruitment, chaperoning, and its
final deposition onto chromatin (Figure 2B) [71,74]. H3.3, together with its chaperones ATRX,
DAXX, HIRA, and DEK, are binding partners of PML NBs. DAXX and ATRX can deposit H3.3 in
the pericentric chromatin of heterochromatin in somatic cells. However, in embryonic stem
cells, PML-facilitated deposition occurs in the telomere region [71,75,76]. Loss of PML can induce telomere dysfunction [71]. In parallel, DEK can control the chromatin distribution of H3.3
[77]. This in turn helps to regulate chromatin architecture and integrity. Moreover, DAXX can assist
the recruitment of H3.3 into PML NBs before its deposition onto chromatin [74]. This implies that
PML might be able to organize chromatin domains via H3.3 recruitment. In addition, PML depletion not only impairs H3.3 deposition in PML-associated domains but also alters the heterochromatic state of PML-associated domains by transforming the balance of histone H3 methylation
Trends in Cancer, Month 2020, Vol. xx, No. xx
5
Trends in Cancer
[78]. Notably, loss of DAXX and ATRX causes chromosome instability and reduces the survival of
patients with pancreatic neuroendocrine tumors [79].
PML NBs and Epigenetic Regulation
PML NBs can accumulate at specific gene loci where they contribute to epigenetic regulation by
orchestrating DNA methylation and chromatin remodeling (Figure 2C). In the pathological condition of ICF (immunodeficiency, centromere, and facial abnormalities) syndrome, giant HP1 PML
bodies packed with satellite DNA can be observed [80]. In this DNA–protein supra-assembly,
the remodeling of heterochromatin in G2 phase is thought to be regulated by the interplay between PML NBs, HP1 proteins, and hypomethylation of satellite DNA. Consistently, chromatinremodeling proteins in HP1 PML bodies fail to accumulate around satellite DNA in PML-deficient
NB4 cells [80]. In addition, PML-mediated DNA modification might be an important factor in
cancer therapies [80]. In response to chemotherapy, PML can recruit dioxygenase TET2 to
enhance 5-hydroxymethylcytosine (5hmC) formation and subsequent DNA demethylation, leading to reactivation of methylation-silenced genes and impaired cell proliferation [81].
PML NBs Are Involved in the DNA Damage Response and Repair To Maintain Genome Stability
Numerous studies show that PML NBs are involved in DNA damage sensing and repair processes (Figure 2D) [82–84]. DNA damage sensors including MRE11, NBS1, CHK2, ATM, and
ATR are closely linked to PML NBs. In response to DNA damage, PML NBs are upregulated
with an increased NB population and distribution in the nucleus. PTMs of PML partner proteins
are also regulated by ATM and ATR kinases [82]. When DNA double-strand breaks (DSBs)
occur, the MRE11/RAD50/NBS1 complex (MRN) can recognize the DNA damage, activate
ATM to phosphorylate histone H2AX (γ-H2AX), and recruit 53BP1, a protein that accumulates
within PML NBs and contributes to DSB repair [85,86]. PML NB integrity is important for ATM
activation and its subsequent ATM-dependent phosphorylation. Furthermore, DSBs can be eliminated via either non-homologous end-joining (NHEJ) or homologous recombination repair (HRR)
pathways. Most players in these two pathways (including 53BP1 in NHEJ, and BRCA1, BLM,
and RAD51 in HRR) are all localized to PML NBs, reiterating the importance of PML in genome
organization and stability [11,87]. A recent study shows that PML NB integrity is required for functional crosstalk between DNA repair proteins 53BP1 and BRCA1, and this in turn ensures correct
switching between the NHEJ and HRR pathways [83]. In addition, the interplay between BLM,
RAD51, and PML NBs is also crucial for proper DNA damage sensing and repair in S/G2
phase [35,88]. Notably, aberrant overexpression of PML results in enlarged PML NBs, which
have a smaller population in the nucleus. This reduction may alter PML–partner protein interactions, leading to a decreased HRR-mediated DNA damage response, suggesting that HRR is
dependent not only on the presence of PML but also on NB dynamics [89].
In the absence of DNA damage, PML NBs may also act as an important depot for factors that
maintain genome stability. For example, key players in DNA damage responses, RAP80 and
TRAIP, are retained in NBs before their translocalization to genomic lesions when damage occurs
[90]. SLX4, which is localized in PML NBs via SUMO–SIM interactions, also plays a key role in
maintaining genome stability [91]. Loss of the SUMO–SIM interaction in SLX4 not only impairs
its location to NBs but also disables its activity in the DNA damage response.
ALT-Associated PML Bodies (APBs) in Telomere Maintenance
Telomere length is an important marker in aging and cancer-related diseases. Tumor cells can
elongate their chromosomal ends by an ALT mechanism [92]. ALT-positive cell lines are characterized by extensive genomic instability, aberrant G2/M checkpoint, and abnormal DSB repair
kinetics [93]. In these cancer cells, PML is also crucial for ALT regulation. PML, together with
6
Trends in Cancer, Month 2020, Vol. xx, No. xx
Trends in Cancer
NBS1, MRE11, RAD51, RAD52, TRF1/2, and telomeric DNA, gives rise to a new form of PML
interactosome, termed the ALT-associated PML body (APB) [94,95] (Figure 2E). PML in
APBs can contribute to telomere length maintenance via recruitment of the BLM–TOP3A–RMI
(BTR) complex to ALT telomere ends, thus promoting ALT phenotypes including C-circle formation and G2 telomere synthesis [96]. It has recently been demonstrated that telomere clustering in
tumors cells can promote ALT via mitotic DNA synthesis (MiDAS) [97]. Overexpression of the PML
binding partners BLM and RAD52 enhances APB formation, telomere clustering, and MiDAS at
telomeres [97]. By contrast, overexpression of another PML binding partner, SLX4, suppresses
telomere extension, APBs, and C-circles [98]. These results suggest that the BLM/RAD52–
PML interaction, which is antagonized by SLX4–PML engagement, plays an important regulatory
role in APB function and dynamics (Figure 2E). In addition, TSPYL5 recruitment by PML NBs can
prevent POT1 (protection of telomeres 1) from poly-ubiquitination and proteasomal degradation,
suggesting that TSPYL5 could a promising target in ALT cancers [99].
Targeted Regulation of Genome Organization Using a PML NB-Based Approach
Genome organization within the nucleus is essential for gene transcription and expression under
physiological and pathological conditions. Taking advantage of PML-driven genome organization, Wang and coworkers engineered a CRISPR genome organization (CRISPR-GO) system
to regulate the spatial positioning of genomic loci relative to distinct nuclear compartments including PML NBs [100]. The CRISPR-GO PML system is chemically inducible and reversible, and can
not only be employed to investigate spatial genome organization and function but could also play
a promising role in therapies targeting PML NBs.
PML and the TRIM Superfamily
Among the RBCC motif, RING and B-box are cysteine‐rich zinc‐binding domains. TRIM proteins
regulate many different cellular processes and pathways involved in innate immunity, antiviral defense, development and differentiation, signaling, and cancer progression [22]. PML/TRIM19 is
one of few TRIM sequences that can polymerize into a megaDalton subcellular compartment.
Furthermore, compared with other TRIMs (most of which belong to the ubiquitin pathway), it is
active in SUMOylation signaling and often recognized as the SUMO E3 [101]. In TRIMs, RINGdependent E3 ubiquitin-ligase activity is frequently observed. In TRIM5α/23/25, RING dimerization is thought be essential for ubiquitin E3 activity [102–104]. In marked contrast, PML RING
adopts a different pattern of oligomerization. A total of 308 772 RING domains have so far
been reported in the RING superfamily (containing 276 130 proteins) (SMART database).
Among these RING molecules, PML RING appears to be unique in two-fold: (i) it interacts with
SUMO E2 ligase, UBC9, and hence is considered to be a SUMO E3; (ii) the L73 and F52QF54 motifs that are exclusively observed in PMLs, and not in other TRIMs, enable the unprecedented PML
RING tetramerization (Figure 3). More importantly, as monitored by FRAP (fluorescence recovery
after photobleaching) and mammalian two-hybrid assays, it has been demonstrated that the
RING tetramerization is important for UBC9 recruitment in which the L73–L73 dimeric interface
might be the docking site of the SUMO E2 [18]. These observations have led to the proposal
that TRIM evolution might represent an interesting new twist in PML/TRIM19 biology. Alternation
of protein oligomerization/assembly might be the key structural determinant that endows PML
with a new function in SUMOylation and related signaling. In support, a unique B-box-driven oligomerization has recently been reported in PML [19]. This again highlights the complexity of PML
NBs biogenesis.
PML Oligomerization and Leukemogenesis
Abnormal PML/RARα expression is often associated with APL patients. The dominant negative
interaction/hijack between PML and PML/RARα significantly disrupts PML–PML engagement
Trends in Cancer, Month 2020, Vol. xx, No. xx
7
Trends in Cancer
(A)
UBC9
90°
UBC9
(B)
PML
TRIM5
TRIM25
TRIM32
TRIM37
TRIM39
TRIM56
TRIM8
TRIM13
TRIM26
TRIM59
TRIM1
TRIM4
TRIM6
TRIM10
TRIM11
TRIM17
TRIM18
TRIM21
TRIM22
TRIM31
TRIM34
TRIM35
TRIM38
TRIM40
TRIM50
TRIM58
TRIM60
TRIM62
TRIM65
TRIM68
MEPAPARSPRPQQDPARPQEPTMPPPETPSEGRQPSPSPSPTERAPASEEEFQFLRCQQCQAEAK----CPKLLPCLHTLCSGCLEA---------------SGMQCPICQAPWPLGAD--TPALDNVFFESLQRRLSVY
--------------------------------------MASG-ILVNVKEE---VTCPICLELLTQ----PLSLDCGHSFCQACLTANHKKSML-D-----KGESSCPVCRISYQPE-N----IRPNRHVANIVEKLREV
-----------------------------------------MAELCPLAEE---LSCSICLEPFKE----PVTTPCGHNFCGSCLNETWAVQ---------GSPYLCPQCRAVYQARPQ----LHKNTVLCNVVEQFLQA
----------------------------------MAAAAASHLNLDALREV---LECPICMESFTEEQLRPKLLHCGHTICRQCLEKLLASS---------INGVRCPFCSKITRIT--SLTQLTDNLTVLKIIDTAGLS
---------------------------------------MDEQSVESIAEV---FRCFICMEKLRDARLC---PHCSKLCCFSCIRRWLTEQ-----------RAQCPHCRAPLQLREL--VNCRWAEEVTQQLDTLQLC
---------------------MAET-SL---LEAGASAASTAAALENLQVE---ASCSVCLEYLKE----PVIIECGHNFCKACITRWWED----L-----ERDFPCPVCRKTSRYR-S----LRPNRQLGSMVEIAKQL
---------------------------M---VSHGSSPSL---LEALSSDF---LACKICLEQLRA----PKTLPCLHTYCQDCLAQLAD-----------GGRVRCPECRETVPVPPEGVASFKTNFFVNGLLDLVKAR
--------------------------------------MAE-NWKNCFEEE---LICPICLHVFVE----PVQLPCKHNFCRGCIGEAWAKD---------SGLVRCPECNQAYNQKPG----LEKNLKLTNIVEKFNAL
--------------------------------------------MELLEED---LTCPICCSLFDD----PRVLPCSHNFCKKCLEGILEGSVRNSLWRPA--PFKCPTCRKE--TSATGINSLQVNYSLKGIVEKYNKI
--------------------------------------MATSAPLRSLEEE---VTCSICLDYLRD----PVTIDCGHVFCRSCTTDVRPISG---------SRPVCPLCKKPFKKE-N----IRPVWQLASLVENIERL
--------------------------------------------MHNFEEE---LTCPICYSIFED----PRVLPCSHTFCRNCLENILQASGNFYIWRPLRIPLKCPNCRSITEIAPTGIESLPVNFALRAIIEKYQQE
---------------------MGESPAS---VVLNASGGLFSLKMETLESE---LTCPICLELFED----PLLLPCAHSLCFSCAHRILVSSCSSGESIEPITAFQCPTCRYVISLNHRGLDGLKRNVTLQNIIDRFQKA
------------------------------------------MEAEDIQEE---LTCPICLDYFQD----PVSIECGHNFCRGCLHRNWAP----G-----GGPFPCPECRHPSAPA-A----LRPNWALARLTEKTQRR
--------------------------------------MTSP-VLVDIREE---VTCPICLELLTE----PLSIDCGHSFCQACITPNGRESVIGQ-----EGERSCPVCQTSYQPG-N----LRPNRHLANIVRRLREV
--------------------------------------MASAASVTSLADE---VNCPICQGTLRE----PVTIDCGHNFCRACLTRYCEIPGPDL-----EESPTCPLCKEPFRPG-S----FRPNWQLANVVENIERL
--------------------------------------MAAPDLSTNLQEE---ATCAICLDYFTD----PVMTDCGHNFCRECIRRCW----GQP-----EGPYACPECRELSPQR-N----LRPNRPLAKMAEMARR--------------------------------------MEAVELARKLQEE---ATCSICLDYFTD----PVMTTCGHNFCRACIQLSWEKARGKKGRRKRKGSFPCPECREMSPQR-N----LLPNRLLTKVAEMAQQ--------------------------------------------METLESE---LTCPICLELFED----PLLLPCAHSLCFNCAHRILVSHCATNESVESITAFQCPTCRHVITLSQRGLDGLKRNVTLQNIIDRFQKA
--------------------------------------MASAARLTMMWEE---VTCPICLDPFVE----PVSIECGHSFCQECISQVG------K-----GGGSVCPVCRQRFLLK-N----LRPNRQLANMVNNLKEI
--------------------------------------MDFS-VKVDIEKE---VTCPICLELLTE----PLSLDCGHSFCQACITAKIKESVIIS-----RGESSCPVCQTRFQPG-N----LRPNRHLANIVERVKEV
--------------------------------------MASGQFVNKLQEE---VICPICLDILQK----PVTIDCGHNFCLKCITQIGETS---------CGFFKCPLCKTSVRKN-A----IRFNSLLRNLVEKIQAL
--------------------------------------MASK-ILLNVQEE---VTCPICLELLTE----PLSLDCGHSLCRACITVSNKEAVTSM-----GGKSSCPVCGISYSFE-H----LQANQHLANIVERLKEV
---------------------------------MERSPDVSPGPSRSFKEE---LLCAVCYDPFRD----AVTLRCGHNFCRGCVSRCWEV----------QVSPTCPVCKDRASPA-D----LRTNHTLNNLVEKLLRE
--------------------------------------MASTTSTKKMMEE---ATCSICLSLMTN----PVSINCGHSYCHLCITDFFKNPSQKQ---LRQETFCCPQCRAPFHMD-S----LRPNKQLGSLIEALKET
----------------------------------------MIPLQKDNQEE---GVCPICQESLKE----AVSTNCGHLFCRVCLTQHVEKASA-------SGVFCCPLCRKPCSEE-V----L-----------------------------------------------------MAWQVSLLELEDW---LQCPICLEVFKE----PLMLQCGHSYCKGCLVSLSCH----L-----DAELRCPVCRQAVDGS-S----SLPNVSLARVIEALRLP
--------------------------------------MAWAPPGERLRED---ARCPVCLDFLQE----PVSVDCGHSFCLRCISEFCEKSDGAQ-----GGVYACPQCRGPFRPS-G----FRPNRQLAGLVESVRR--------------------------------------MEFVTALVNLQEE---SSCPICLEYLKD----PVTINCGHNFCRSCLSVSWKD----L-----DDTFPCPVCRFCFPYK-S----FRRNPQLRNLTEIAKQL
-------------------------------------------MACSLKDE---LLCSICLSIYQD----PVSLGCEHYFCRRCITEHWVRQEA-------QGARDCPECRRTFAEP-A----LAPSLKLANIVERYSSF
------------------------------------------MAAQLLEEK---LTCAICLGLYQD----PVTLPCGHNFCGACIRDWWDRC-----------GKACPECREPFPDGAE----LRRNVALSGVLEVVRAG
--------------------------------------MDPTALVEAIVEE---VACPICMTFLRE----PMSIDCGHSFCHSCLSGLWEIPGESQ-----NWGYTCPLCRAPVQPR-N----LRPNWQLANVVEKVRLL
SUMO E3 ligase
Ubiquitin E3 ligases
Trends in Cancer
Figure 3. Oligomerization Underlies the Specificity of Promyelocytic Leukemia Protein (PML) Recruitment among TRIM Superfamily Proteins. (A) Putative
binding between PML (surface diagram, green/blue/yellow/cyan for each monomer) and SUMO E2 ligase UBC9 (cartoon diagram, red). (B) Sequence alignment between
the SUMO E3 ligase PML/TRIM19 and other ubiquitin E3 ligases in TRIMs. The F52QF54 and L73 sequences, that are exclusively associated with PMLs, are colored in red.
The invariant Zn binding site is highlighted with blue asterisks underneath the protein sequences.
and the formation of PML NBs, and this is thought to be important in tumor-suppressive processes including cellular apoptosis, senescence, and angiogenesis, and also impairs the quality
of DNA damage repair via the NHEJ and HRR pathways [105]. In parallel, PML–RARα gain of
function is also an important driving factor in APL leukemogenesis. It has been shown that
DAXX recruitment of PML/RARα via K160 SUMOylation (a process regulated by B1 networking)
is crucial for oncogenic transcription and leukemia development [26]. Intriguingly, PML–RARα is
thought to recognize N3000 DNA binding sites via numerous DNA-binding factors (DBFs) including canonical RAREs, RXR, and PU.1 [106,107]. Furthermore, the PML–RARα–DBF complex
might cooperate with corepressor complexes (CoRs) such as the HDAC epigenetic modifiers,
polycomb repressive complexes (PRCs), and DNA methyltransferases [108–111]. Interplay
between PML/RARα, DBF, and CoR trigger aberrated transactivation/repression that results in
leukemia. Recent in vivo studies have shown that L73E and F158E mutations in PML–RARα,
both of which target RBCC oligomerization, abrogate APL leukemogenesis (Figure 4A). This has
led to the proposal that oligomerization might be an important driving factor in APL. Of note,
single-cell RNA-seq analysis of PML–RARα and PML–RARα F158E revealed several previously
unrecognized PML–RARα oligomerization target genes that might underpin APL pathogenesis
8
Trends in Cancer, Month 2020, Vol. xx, No. xx
Trends in Cancer
(A)
100
100
PRL73E (n = 8)
PRF158E (n = 8)
80
Survival (%)
Survival (%)
80
60
40
PR (n = 8)
PR (n = 8)
0
0
0
Log2(fold-change)
40
20
20
(B)
60
100
200
300
400
500
600
0
100
5
4
3
2
1
0
–1
–2
–3
–4
–5
200
300
400
500
Day (s)
Day (s)
Granulocyte
Stem cell
Erythrocyte
PR vs WT
PRF158E vs PR
(C)
PML
RARα
N-mer-driven deregulation
Leukemogenesis
n
Trends in Cancer
Figure 4. Oligomerization-Driven Leukemogenesis. (A) Survival curves of MRP8-driven PML–RARαL73E or PML–
RARαF158E mutant transgenic mice compared with PML–RARα transgenic mice. The PML–RARα fusion is shown as PR in
the figure. The transgenic mice, but not the oligomerization mutants, developed acute promyelocytic leukemia (APL).
(B) Differential gene expression analysis of WT, PML–RARα, and PML–RARαF158E transgenic mice reveals novel
oligomerization target genes in leukemogenesis. Representative gene expression profiles in granulocytes, stem cells, and
erythrocytes (i.e., Trib3, Atf5, and Ifitm1 [162–179]) are shown. The overlap between PML–RARα versus WT upregulation
and PML–RARαF158E versus PML–RARα downregulation suggest that PML–RARα oligomerization is implicated in APL leukemogenesis. (C) A revised model of PML–RARα oligomerization-driven leukemogenesis. PML polymerization (i.e., N-mer
formation) is essential for subsequent abnormal transactivation and leukemia development.
(Figure 4B). Most of these newly identified genes deserve further exploration. Further understanding of these PML–RAR oligomerization target genes will undoubtedly help to uncover the exact
molecular mechanism underpinning oligomerization-driven carcinogenesis (Figure 4C).
Oligomerization Is Important for the Arsenic Response
Treatment with ATO results in a definitive cure rate of N95% in APL patients [14–17,112,113].
ATRA is the principal endogenous ligand for retinoic acid receptor α (RARα). Binding/targeting
between ATRA and RARα reverses PML–RARα-dependent transcription regulation, leading to
proteasome-mediated PML–RARα degradation. This is the molecular basis of ATRA-driven differentiation therapy in APL [114]. By comparison, ATO is thought to enhance PML SUMOylation,
which subsequently leads to self-destruction of the oncogenic fusion via the proteasome pathway
[17,47]. Moreover, ATO-driven PML–RARα degradation also helps to restore the PML NB assembly and normal regulation of PML/P53-mediated apoptosis [115,116]. Hence, the reappearance of
Trends in Cancer, Month 2020, Vol. xx, No. xx
9
Trends in Cancer
PML NBs is also an important factor/regulator in ATO targeted therapy. Based on chemically
modified ATO and PML–RARα mutants that are frequently observed in ATO-resistant APL
patients, it is thought that the RBCC domain might be the ATO binding site [17,117]. Recently,
Wang and coworkers showed that the PML–RARα mutants, L73E and F52E/F54E, display
much less NB reappearance, SUMOylation, and terminal differentiation than wild-type PML–
RARα [18]. This has led to the hypothesis that PML oligomerization might prime the ATO–PML
interaction, and hence could serve as an important factor in targeted therapy (Figure 5).
Oncogenic Oligomerization in Leukemias and Solid Tumors
Numerous studies have highlighted oncogenic oligomerization as a crucial driving factor in hematopoietic malignancies and solid tumors. In leukemias, oligomerization is frequently observed in various
oncogenic fusions such as BCR–ABL, BCR–FGFR1, AML1–ETO, AML–MTG16, PML–RARα,
PLZF–RARα, MLL–GAS7, TEL–AML1, and PAX5–PML [18,19,118–125]. Oligomerization not only
enhances binding affinity against the nascent DNA responsive element (DRE), but also helps
to gain new binding sites compared with the wide-type counterparts. For the XXX-RARα drivers
(XXX for the N-terminal fusion) in APL, almost all the N-terminal partners display oligomerization activity: PML polymerization, PLZF dimerization, NuMA dimerization, and STAT5B tetramerization. Due to
homo-multimerization, PML-RARα inhibits wild-type PML polymerization and NB biogenesis,
RA
RING
B1
B2
Degradation
CC
As2O3 /RA
Cell differentiation
RARD
PML–RARD
UBC9
n
RA
As2O3-mediated polymerization
Other intermolecular linkage
C66 disulfide bridge
As2O3
Putative disulfide bridge
Non-covalent interaction
Trends in Cancer
Figure 5. Promyelocytic Leukemia Protein (PML) Oligomerization Primes Targeted Therapy in Acute
Promyelocytic Leukemia (APL) Treatment. Oligomerization mediated by RING tetramerization and B1 polymerization
at basal level might provide the necessary structural foundation/determinants for the response to arsenic trioxide (As2O3,
ATO). ATO may further enhance PML–RARα polymerization via direct crosslinking and ATO-driven Cys–Cys bond
formation, leading to PML–RARα multimerization. The formation of higher-order polymers may in turn recruit UBC9,
resulting in subsequent SUMOylation/ubiquitination-driven PML–RARα degradation via the proteasome. This ultimately
leads to molecular clearance of the PML–RARα fusion and abrogation of APL. In addition, all-trans retinoic acid (ATRA,
shown as RA), which targets the RARα moiety, contributes to PML–RARα degradation, cell differentiation, and APL therapy.
10
Trends in Cancer, Month 2020, Vol. xx, No. xx
Trends in Cancer
resulting in APL leukemogenesis [105,112]. In recent reports, RING and B1-box-mediated PML–
RARα oligomerization is identified as an important regulator in APL pathogenesis [18,19]. In agreement, the PML CC domain is also significant for transformation and differentiation [126]. PLZF–
RARα homo- and hetero-dimerization with RXRα (retinoid X receptor α) are primarily mediated by
the POZ and RARα domains, respectively [118]. The dimerization of α-helical CC domain in NuMA
is also essential for homodimer formation, transcriptional repression of wild-type RARα, transcriptional
activation of STAT3, and stability of the NuMA–RARα/SMRT complex [127]. STAT5B/RARα
homodimers via the CC domain can inhibit the transcriptional activity of RARα/RXRα and stabilize
the STAT5B–RARα/SMRT complex, contributing to myeloid maturation arrest [128].
Furthermore, in AML it has also been shown that AML1–ETO can form a tetramer via the NHR2
domain [119]. The oligomerization, which is required for ETO, MTGR1, and MTG16 recruitment,
can contribute to AML1–ETO-driven granulocyte differentiation arrest and enhance the clonogenic
potential of primary mouse bone marrow cells [119]. In ALL (acute lymphocytic leukemia) and other
types of leukemias, oncogenic oligomerization is also a common theme. The oligomerization of the
PTD domain in TEL–AML1 is essential for differentiation impairment [124]. The coiled-coil oligomerization domains of MLL–GAS7 and MLL–AF1p in MLL (mixed lineage leukemia ) are necessary and
sufficient for leukemogenic transformation [123]. The fusions BCR–ABL and BCR–FGFR1 in CML
(chronic myeloid leukemia) can also undergo homo-oligomerization via a coiled-coil domain.
Notably, the disruption of coiled-coil interaction significantly impairs their oncogenic activity
[121,122]. Together, these results highlight the importance of multimerization in leukemogenesis.
However, oligomerization is not restricted to blood malignancies. For example, in breast cancer,
the oncogenic activity of the Neu/ErbB-2 receptor tyrosine kinase is often correlated with constitutive dimerization [129]. In addition, V664E in Neu/ErbB-2 promotes receptor dimerization, and
hence its transformation activity [130]. Similar oligomerization schemes can be observed in other
cancer types. For example, the scaffold protein ArgBP2 is thought to be important for pancreatic
cell migration, adhesion, and tumorigenicity [131]. Using a human pancreatic cancer cell model
(MiaPaCa-2 cells), it has been shown that oligomerization, controlled by tyrosine phosphorylation,
is an important regulator for ArgBP2 adaptive capabilities and associated functions/signals in
pancreatic cancer [132]. EML4–AKL fusion was first detected in non-small-cell lung cancer
(NSCLC) patients [133]. Translocations at different points within the EML4 gene result in multiple
variants of EML4–AKL identified in NSCLC [134] and the oligomerization state of the coiled-coil in
N-terminal EML4 is required for oncogenic EML4–ALK activation [135]. A similar oligomerization
strategy was observed in the oncoprotein TPR–MET, which was first detected in a human osteogenic sarcoma cell line [136], and later reported in gastric carcinomas [137,138]. Dimerization of
TPR–MET mediated by a leucine zipper motif of TPR results in constitutive kinase activation of
MET, which is strictly required for transformation [139,140]. In addition, a series of FGFR fusions
(i.e., FGFR–AFF3, FGFR–CASP7, FGFR–CCDC6, FGFR–TACC3, FGFR–BICC1, and SLC45A3–
FGFR, BAG4–FGFR, ERLIN2–FGFR) have been identified in clinic patients with bladder cancer,
oral cancer, lung squamous cell cancer, glioblastoma, thyroid cancer, and prostate cancers
[141]. Most FGFR fusions display oligomerization activity, highlighting a common oligomerization
mechanism in carcinogenesis [141].
PML in Human Cancers beyond APL
PML NBs are implicated in a variety of human cancers ranging from leukemias to solid tumors
(Table 1). This has led to the hypothesis that PML NBs might be important stress regulators in
pathogenic conditions. This is further supported by the observation that, when the Pml gene is
knocked out, Pml−/− mice become more susceptible to infections and tumorigenesis [142,143].
Historically, PML is considered to be a tumor repressor under normal physiological conditions
Trends in Cancer, Month 2020, Vol. xx, No. xx
11
Trends in Cancer
Table 1. PML in Human Cancers Beyond APL
Disease/virus subtypes
PML-related functions
Refs
Chronic myeloid leukemia
(CML)
CML chronic phase (CP) samples express high levels of PML
PML is required for the maintenance of leukemia-initiating cells
(LICs)
[149,150]
Lung cancer
PML can also regulate the tumor microenvironment and immunity in
lung cancer
[148]
Glioblastoma (GBM)
PML can regulate cell migration in primary human GBM cells
Abnormal expression of PML in GBM patient tissue might promote
drug resistance and block drug-induced apoptosis
[151,155]
Triple-negative breast cancer
(TNBC)
Abnormally upregulated PML can enhance cancer-initiating cell
(CIC) activity and metastatic potential in TNBC
Inhibition of PML expression triggers antitumor responses
[152–154]
Hepatocellular carcinoma
(HCC)
PML might produce ATO resistance by upregulating ALDH3A1 in
HCC cells
[156]
Ovarian cancer
OXPHOS metabolism and chemosensitivity depend on
PML–PGC-1α regulation
[157]
Pancreatic cancer
Low PML SUMOylation is involved in gemcitabine and oxaliplatin
resistance of pancreatic ductal adenocarcinoma (PDAC)
[159]
Non-small cell lung
carcinoma (NSCLC)
Increased PML expression regulated by CK2 might sensitize
NSCLC to cisplatin
[158]
Small cell lung carcinoma
Absence of PML is associated with a tumorigenic phenotype
[180]
Multiple myeloma
The inhibitory effects of interferon (IFN)-α on myeloma cells correlate
with PML
[181]
Colorectal cancer
PML is frequently found in tumors with short telomeres and high
proliferation
[182]
Obesity
PML is an energy sensor that adjusts gene expression to regulate
metabolism
[160]
Hepatitis C virus (HCV)
PML is required for HCV production
[161]
Human papillomavirus (HPV)
PML can retain incoming HPV DNA in the nucleus for subsequent
transcription
[183]
Herpes simplex virus 1
(HSV-1)
PML is a major actor in latent/quiescent HSV-1 H3.3
chromatinization
[184]
[144] and PML is often downregulated in various human cancers [145–147]. A recent study has
suggested that PML can also regulate the tumor microenvironment and immunity in lung cancer
[148]. In the development of this disease, PML is negatively regulated by the CRL4WDR4-mediated
ubiquitylation pathway, in which CRL4WDR4 is a newly identified PML ubiquitin ligase. The PML
ubiquitination pathway subsequently can transactivate a series of downstream genes, which in
turn regulate the tumor microenvironment for lung cancer growth, progression, and metastasis
[148]. This has prompted the idea that immune-modulatory approaches can be adopted in the
treatment of lung cancer by targeting PML degradation.
Interestingly, increasing evidence has demonstrated that PML might also act as an oncogenic
driver in carcinogenesis. In leukemia, PML can control cancer stem cell self-renewal [149]. The
occurrence of leukemia relapse could be due to the fact that therapies fail to eradicate quiescent
leukemia-initiating cells (LICs). CML, a paradigmatic hematopoietic stem cell (HSC) disorder,
often relapses after drug withdrawal. This is mainly due to the existence of LICs. According to
clinical analysis, most CML chronic phase (CP) samples express high levels of PML. In marked
contrast, patients with low PML expression display a better clinical outcome. PML deficiency
impairs LIC maintenance, which has a crucial impact on leukemia eradication [149]. More
12
Trends in Cancer, Month 2020, Vol. xx, No. xx
Trends in Cancer
importantly, ATO can downregulate PML, and hence is an effective approach for LIC eradication
[149]. In addition, the PML peroxisome proliferator-activated receptor δ (PPARδ) fatty acid oxidation (FAO) pathway is crucial for HSC maintenance. PML-deficient HSCs exhibit reduced FAO,
implying that inhibitors of FAO may be a promising target for LIC elimination [150].
The oncogenic role of PML is echoed in glioblastoma (GBM), the most common and aggressive
brain cancer. It has been demonstrated that PML can enhance the migration of H-RASV12 neural
progenitor/stem cells (NPCs) via repression of SLIT1, a key regulator of axon guidance [151]. Mice
injected with H-RASV12 Pml−/− cells survive longer than those treated with H-RASV12 Pml+/− cells,
and tumor cells with PML expression display greater invasive activity. Consistently, PML can also
regulate cell migration in primary human GBM cells via SLIT1 repression. The growth of primary
GBM cells is also reduced upon PML knockdown, suggesting that PML might be a promising therapeutic target for GBM [151]. Immunohistochemical analysis of breast cancer biopsies has shown
that aberrant transactivation of PML is enriched in triple-negative breast cancer (TNBC) [152]. The
regulation of cancer metabolism by PML is important for breast cancer cell survival, and abnormally
upregulated PML can enhance cancer-initiating cell (CIC) and metastatic potential in TNBC via
regulation of HIF1A target genes [153]. Inhibition of PML expression triggers antitumor responses
including growth arrest and senescence of TNBC cells, which are associated with decreased
MYC and PIM1 kinase levels, as well as the subsequent accumulation of p27, an important regulator
in cell senescence [154]. More importantly, it has been shown that pharmacological inhibition of PML
with ATO can delay tumor growth and impair TNBC metastasis [153].
PML is also involved in resistance/sensitivity to therapy. The combination of ATO with mTOR
kinase and EGFR tyrosine kinase inhibitors (TKIs) can reduce drug resistance or increase drug
sensitivity, leading to a better therapeutic effect. The abnormal expression of PML in GBM patient
tissue might promote drug resistance as well as blocking drug-induced apoptosis [155]. Nuclear
PML expression in GBM is promoted by mTOR inhibitors and EGF receptor (EGFR) inhibitors that
block downstream mTOR signaling [155]. ATO inhibits PML expression, helping to reverse mTOR
kinase inhibitor resistance in vivo, resulting in tumor cell death in mice [155]. Furthermore, ATO is
surprisingly effective in hepatocellular carcinoma (HCC) patients with negative PML expression,
but not in patients with positive PML expression. It is possible that PML might produce ATO
resistance by upregulating ALDH3A1 in HCC cells [156]. Therefore, ATO combined with an
ALDH3A1 inhibitor is considered to be a better target therapy in HCC patients with abnormal
PML expression [156]. In high-grade serious ovarian cancer (HGSOC), PML is thought to
enhance conventional chemotherapies under conditions of high oxidative phosphorylation
(OXPHOS) [157]. Interestingly, increased PML expression regulated by protein kinase CK2
might sensitize NSCLC cells to cisplatin, the main therapy for this cancer type [158]. In addition,
low PML SUMOylation was found to be involved in gemcitabine and oxaliplatin resistance of
pancreatic ductal adenocarcinoma (PDAC) [159].
In addition to cancer, PML is also a crucial factor in the occurrence and development of other diseases such as metabolic disease and viral infections. In metabolic disease, mice with Pml deletion
show altered gene expression in skeletal muscle, adipose tissue, and liver, an increased rate of
fatty acid metabolism, constitutive AMPK activation, and insulin resistance [160]. The increased
rate of energy expenditure in Pml−/− mice is thought to protect mice from obesity, suggestive of
a regulatory role of PML in energy balance [160]. Therefore, PML might also serve as a useful target in obesity-related disease. In addition, during viral infection, PML is thought to play a crucial
role in viral production and latency. Hepatitis C virus (HCV) is a causative agent of chronic hepatitis, liver cirrhosis, and HCC. It has been shown that PML and its related proteins such as INI1
and DDX5 are required for HCV production [161].
Trends in Cancer, Month 2020, Vol. xx, No. xx
13
Trends in Cancer
Concluding Remarks
Outstanding Questions
Although the PML nuclear body was first observed in the 1960s, its mechanism of assembly remains
poorly understood. Answering the question of how a 70 kDa PML can give rise to a subcellular
organelle remains a Holy Grail of the PML field (see Outstanding Questions). The RBCC-mediated
oligomerization recently highlighted in PML NBs highlights how a protein might evolve via the multiplication of its polypeptide chains in 3D space. Like other membraneless nuclear bodies such as
P granules and Cajal bodies, the dynamics of PML NB assembly, as observed by ultracentrifugation
and FRAP analysis, might reflect phase separation, and hence is worthy of more vigorous investigation. More importantly, RING tetramerization is thought to be important for UBC9-mediated
SUMOylation, and may therefore be crucial for leukemogenesis and targeted therapy. However,
the exact interaction between PML and UBC9 is not yet characterized. Addressing these issues
will undoubtedly lead to a better understanding of PML nuclear body oligomerization/biogenesis,
PML-driven genome organization, and carcinogenesis (see Outstanding Questions).
Under pathological conditions, malfunction of PML NBs is frequently associated with carcinogenesis.
As demonstrated in APL, AML, GBM, and NSCLC, targeted therapy with ATO against PML oligomerization is a useful strategy to reduce recurrence and metastasis. Furthermore, the oligomerization
scheme is widely observed in other leukemogenic fusions and solid tumors, reiterating the important
concept/recognition of oncogenic multimerization in carcinogenesis. This has led to the hypothesis
that oncogenic oligomerization may represent a promising target in the treatment of leukemias and
solid tumors.
Acknowledgments
This work was supported by research grants 81970132, 81770142, 81370620, 81570120, 31070645, 81800144, and
31800642 from National Natural Science Foundation of China, grant 20152504 from the Shanghai Municipal Education
(SME) Commission – Gaofeng Clinical Medicine Grant Support, the Program for Professor of Special Appointment
(Eastern Scholar) at Shanghai Institute of Higher Learning, grant 11JC1407200 from the Shanghai Municipal Science
and Technology Commission (SMSTC), grant 12ZZ109 from the SME, a Program for New Century Excellent University
Talents award (NCET-10–9571), the Samuel Waxman Cancer Research Foundation, and the Shanghai Guangci
Translational Medical Research Development Foundation.
References
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
14
Bray, F. et al. (2018) Global cancer statistics 2018:
GLOBOCAN estimates of incidence and mortality worldwide
for 36 cancers in 185 countries. CA Cancer J. Clin. 68,
394–424
Jensen, K. et al. (2001) PML protein isoforms and the RBCC/
TRIM motif. Oncogene 20, 7223–7233
Weidtkamp-Peters, S. et al. (2008) Dynamics of component
exchange at PML nuclear bodies. J. Cell Sci. 121, 2731–2743
Shen, T.H. et al. (2006) The mechanisms of PML-nuclear body
formation. Mol. Cell 24, 331–339
Wiesmeijer, K. et al. (2002) Mobile foci of Sp100 do not contain
PML: PML bodies are immobile but PML and Sp100 proteins
are not. J. Struct. Biol. 140, 180–188
Ito, K. et al. (2012) A PML–PPARdelta pathway for fatty acid
oxidation regulates hematopoietic stem cell maintenance.
Nat. Med. 18, 1350–1358
Lallemand-Breitenbach, V. and de The, H. (2010) PML nuclear
bodies. Cold Spring Harb. Perspect. Biol. 2, a000661
Bernardi, R. et al. (2004) PML regulates p53 stability by sequestering Mdm2 to the nucleolus. Nat. Cell Biol. 6, 665–672
Varadaraj, A. et al. (2007) Evidence for the receipt of DNA damage stimuli by PML nuclear domains. J. Pathol. 211, 471–480
Bernardi, R. and Pandolfi, P.P. (2007) Structure, dynamics and
functions of promyelocytic leukaemia nuclear bodies. Nat. Rev.
Mol. Cell Biol. 8, 1006–1016
Guan, D. and Kao, H.Y. (2015) The function, regulation and
therapeutic implications of the tumor suppressor protein.
PML. Cell Biosci. 5, 60
Trends in Cancer, Month 2020, Vol. xx, No. xx
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
Nisole, S. et al. (2005) TRIM family proteins: retroviral restriction
and antiviral defence. Nat. Rev. Microbiol. 3, 799–808
de The, H. et al. (1990) The t(15;17) translocation of acute
promyelocytic leukaemia fuses the retinoic acid receptor
alpha gene to a novel transcribed locus. Nature 347, 558–561
Huang, M. et al. (1988) Use of all trans retinoic acid in the treatment of acute promyelocytic leukaemia. Blood 72, 567–572
Chen, G.Q. et al. (1997) Use of arsenic trioxide (As2O3) in the
treatment of acute promyelocytic leukemia (APL). I. As2O3 exerts
dose-dependent dual effects on APL cells. Blood 89,
3345–3353
Hu, J. et al. (2009) Long-term efficacy and safety of all-trans
retinoic acid/arsenic trioxide-based therapy in newly diagnosed
acute promyelocytic leukemia. Proc. Natl. Acad. Sci. U. S. A.
106, 3342–3347
Zhang, X.W. et al. (2010) Arsenic trioxide controls the fate of the
PML–RARalpha oncoprotein by directly binding PML. Science
328, 240–243
Wang, P. et al. (2018) RING tetramerization is required for nuclear
body biogenesis and PML sumoylation. Nat. Commun. 9, 1277
Li, Y. et al. (2019) B1 oligomerization regulates PML nuclear body
biogenesis and leukemogenesis. Nat. Commun. 10, 3789
Sahin, U. et al. (2014) Oxidative stress-induced assembly of
PML nuclear bodies controls sumoylation of partner proteins.
J. Cell Biol. 204, 931–945
Meroni, G. and Diez-Roux, G. (2005) TRIM/RBCC, a novel
class of 'single protein RING finger' E3 ubiquitin ligases.
Bioessays 27, 1147–1157
How does a 70 kDa PML oligomerize
into a subcellular organelle?
How does phase separation facilitate
PML NB biogenesis and resultant
polyvalent signaling?
How does PML engage UBC9 and
other partner proteins?
How do PML NBs contribute to
genome organization?
Is oncogenic oligomerization a common
mechanism in tumorigenesis?
Can oncogenic oligomerization be
targeted in cancer treatment?
Can PML NBs be targeted in PMLrelated cancers?
Trends in Cancer
22.
23.
24.
25.
26.
27.
28.
29.
30.
31.
32.
33.
34.
35.
36.
37.
38.
39.
40.
41.
42.
43.
44.
45.
46.
47.
48.
Hatakeyama, S. (2011) TRIM proteins and cancer. Nat. Rev.
Cancer 11, 792–804
Yudina, Z. et al. (2015) RING dimerization links higher-order
assembly of TRIM5alpha to synthesis of K63-linked
polyubiquitin. Cell Rep. 12, 788–797
Wagner, J.M. et al. (2016) Mechanism of B-box 2 domainmediated higher-order assembly of the retroviral restriction
factor TRIM5alpha. Elife 5, e16309
Sanchez, J.G. et al. (2014) The tripartite motif coiled-coil is an
elongated antiparallel hairpin dimer. Proc. Natl. Acad. Sci. U. S. A.
111, 2494–2499
Zhu, J. et al. (2005) A sumoylation site in PML/RARA is essential for leukemic transformation. Cancer Cell 7, 143–153
Mao, Y.S. et al. (2011) Biogenesis and function of nuclear bodies.
Trends Genet. 27, 295–306
Decker, C.J. and Parker, R. (2012) P-bodies and stress
granules: possible roles in the control of translation and
mRNA degradation. CSH Perspect. Biol. 4, a012286
Dellaire, G. and Bazett-Jones, D.P. (2004) PML nuclear bodies:
dynamic sensors of DNA damage and cellular stress.
Bioessays 26, 963–977
Muratani, M. et al. (2002) Metabolic-energy-dependent movement of PML bodies wthin the mammalian cell nucleus. Nat.
Cell Biol. 4, 106–110
Muller, S. et al. (1998) Conjugation with the ubiquitin-related
modifier SUMO-1 regulates the partitioning of PML within the
nucleus. EMBO J. 17, 61–70
Kamitani, T. et al. (1998) Identification of three major
sentrinization sites in PML. J. Biol. Chem. 41, 26675–26682
Lallemand-Breitenbach, V. et al. (2001) Role of promyelocytic
leukemia (PML) sumolation in nuclear body formation, 11S
proteasome recruitment, and As2O3-induced PML or PML/
retinoic acid receptor alpha degradation. J. Exp. Med. 193,
1361–1372
Yeh, E.T. (2009) SUMOylation and de-SUMOylation: wrestling
with life's processes. J. Biol. Chem. 284, 8223–8227
Han, Y. et al. (2010) SENP3-mediated de-conjugation of
SUMO2/3 from promyelocytic leukemia is correlated with accelerated cell proliferation under mild oxidative stress. J. Biol.
Chem. 285, 12906–12915
Ishov, A.M. et al. (1999) PML is critical for ND10 formation and
recruits the PML-interacting protein Daxx to this nuclear structure when modified by SUMO-1. J. Cell Biol. 147, 221–234
Zhong, S. et al. (2000) Role of SUMO-1-modified PML in
nuclear body formation. Blood 95, 2748–2752
Banani, S.F. et al. (2016) Compositional control of phaseseparated cellular bodies. Cell 166, 651–663
Banani, S.F. et al. (2017) Biomolecular condensates: organizers of cellular biochemistry. Nat. Rev. Mol. Cell Biol. 18,
285–298
Brangwynne, C.P. et al. (2009) Germline P granules are liquid
droplets that localize by controlled dissolution/condensation.
Science 324, 1729–1732
Weber, S.C. and Brangwynne, C.P. (2015) Inverse size scaling
of the nucleolus by a concentration-dependent phase transition.
Curr. Biol. 25, 641–646
Singer, A.B. and Gall, J.G. (2011) An inducible nuclear body in
the Drosophila germinal vesicle. Nucleus 2, 403–409
Yang, S. et al. (2002) PML-dependent apoptosis after DNA
damage is regulated by the checkpoint kinase hCds1/Chk2.
Nat. Cell Biol. 4, 865–870
Scaglioni, P.P. et al. (2006) A CK2-dependent mechanism for
degradation of the PML tumor suppressor. Cell 126, 269–283
Hayakawa, F. et al. (2008) Acetylation of PML is involved in histone deacetylase inhibitor-mediated apoptosis. J. Biol. Chem.
283, 24420–24425
Guan, D. et al. (2014) Deacetylation of the tumor suppressor
protein PML regulates hydrogen peroxide-induced cell death.
Cell Death Dis. 5, e1340
Lallemand-Breitenbach, V. et al. (2008) Arsenic degrades PML
or PML–RARalpha through a SUMO-triggered RNF4/ubiquitinmediated pathway. Nat. Cell Biol. 10, 547–555
Louria-Hayon, I. et al. (2009) E6AP promotes the degradation
of the PML tumor suppressor. Cell Death Differ. 16,
1156–1166
49.
50.
51.
52.
53.
54.
55.
56.
57.
58.
59.
60.
61.
62.
63.
64.
65.
66.
67.
68.
69.
70.
71.
72.
73.
74.
Wolyniec, K. et al. (2012) E6AP ubiquitin ligase regulates PMLinduced senescence in Myc-driven lymphomagenesis. Blood
120, 822–832
Hayakawa, F. and Privalsky, M.L. (2004) Phosphorylation of
PML by mitogen-activated protein kinases plays a key role in
arsenic trioxide-mediated apoptosis. Cancer Cell 5, 389–401
Cappadocia, L. et al. (2015) Structural and functional characterization of the phosphorylation-dependent interaction between PML and SUMO1. Structure 23, 126–138
Chang, C.C. et al. (2011) Structural and functional roles of
Daxx SIM phosphorylation in SUMO paralog-selective binding
and apoptosis modulation. Mol. Cell 42, 62–74
Ullmann, R. et al. (2012) An acetylation switch regulates
SUMO-dependent protein interaction networks. Mol. Cell 46,
759–770
Mascle, X.H. et al. (2020) Acetylation of SUMO1 alters interactions with the SIMs of PML and Daxx in a protein-specific
manner. Structure 28, 157–168
Hendriks, I.A. et al. (2017) Site-specific mapping of the human
SUMO proteome reveals co-modification with phosphorylation.
Nat. Struct. Mol. Biol. 24, 325–336
Pearson, M. and Pelicci, P.G. (2001) PML interaction with p53
and its role in apoptosis and replicative senescence. Oncogene
20, 7250–7256
Hofmann, T.G. et al. (2001) Regulation of p53 activity by its interaction with homeodomain- interacting protein kinase-2. Nat.
Cell Biol. 10, 10
Li, Q. et al. (2011) AXIN is an essential co-activator for the
promyelocytic leukemia protein in p53 activation. Oncogene
30, 1194–1204
Louria-Hayon, I. et al. (2003) The promyelocytic leukemia
protein protects p53 from Mdm2-mediated inhibition and
degradation. J. Biol. Chem. 278, 33134–33141
Langley, E. et al. (2002) Human SIR2 deacetylates p53 and
antagonizes PML/p53-induced cellular senescence. EMBO J.
21, 2383–2396
Yang, Q. et al. (2013) BMK1 is involved in the regulation of p53
through disrupting the PML–MDM2 interaction. Oncogene 32,
3156–3164
Wan, J. et al. (2019) Mad1 destabilizes p53 by preventing PML
from sequestering MDM2. Nat. Commun. 10, 1540
Cremer, T. and Cremer, C. (2001) Chromosome territories, nuclear architecture and gene regulation in mammalian cells. Nat.
Rev. Genet. 2, 292–301
Wang, J. et al. (2004) Promyelocytic leukemia nuclear bodies
associate with transcriptionally active genomic regions. J. Cell
Biol. 164, 515–526
Shastrula, P.K. et al. (2019) PML is recruited to heterochromatin during S phase and represses DAXX-mediated histone H3.3
chromatin assembly. J. Cell Sci. 132
Kumar, P.P. et al. (2007) Functional interaction between PML
and SATB1 regulates chromatin-loop architecture and transcription of the MHC class I locus. Nat. Cell Biol. 9, 45–56
Ching, R.W. et al. (2005) PML bodies: a meeting place for
genomic loci? J. Cell Sci. 118, 847–854
Chang, K.-S. et al. (1995) The PML gene encodes a phosphoprotein associated with the nuclear matrix. Blood 85,
3646–3653
Dellaire, G. et al. (2006) The number of PML nuclear bodies increases in early S phase by a fission mechanism. J. Cell Sci.
119, 1026–1033
Zhong, S. et al. (1999) A role for PML and the nuclear body in
genomic stability. Oncogene 18, 7941–7947
Chang, F.T. et al. (2013) PML bodies provide an important platform for the maintenance of telomeric chromatin integrity in
embryonic stem cells. Nucleic Acids Res. 41, 4447–4458
Goldberg, A.D. et al. (2010) Distinct factors control histone
variant H3.3 localization at specific genomic regions. Cell
140, 678–691
Pchelintsev, N.A. et al. (2013) Placing the HIRA histone chaperone complex in the chromatin landscape. Cell Rep. 3,
1012–1019
Delbarre, E. et al. (2013) DAXX-dependent supply of soluble
(H3.3–H4) dimers to PML bodies pending deposition into
chromatin. Genome Res. 23, 440–451
Trends in Cancer, Month 2020, Vol. xx, No. xx
15
Trends in Cancer
75.
76.
77.
78.
79.
80.
81.
82.
83.
84.
85.
86.
87.
88.
89.
90.
91.
92.
93.
94.
95.
96.
16
Lewis, P.W. et al. (2010) Daxx is an H3.3-specific histone
chaperone and cooperates with ATRX in replicationindependent chromatin assembly at telomeres. Proc. Natl.
Acad. Sci. U. S. A. 107, 14075–14080
Eustermann, S. et al. (2011) Combinatorial readout of histone H3
modifications specifies localization of ATRX to heterochromatin.
Nat. Struct. Mol. Biol. 18, 777–782
Ivanauskiene, K. et al. (2014) The PML-associated protein DEK
regulates the balance of H3.3 loading on chromatin and is important for telomere integrity. Genome Res. 24, 1584–1594
Delbarre, E. et al. (2017) PML protein organizes heterochromatin domains where it regulates histone H3.3 deposition by
ATRX/DAXX. Genome Res. 27, 913–921
Marinoni, I. et al. (2014) Loss of DAXX and ATRX are associated
with chromosome instability and reduced survival of patients with
pancreatic neuroendocrine tumors. Gastroenterology 146,
453–460.e5
Luciani, J.J. et al. (2006) PML nuclear bodies are highly
organised DNA–protein structures with a function in heterochromatin remodelling at the G2 phase. J. Cell Sci. 119,
2518–2531
Song, C. et al. (2018) PML recruits TET2 to regulate DNA modification and cell proliferation in response to chemotherapeutic
agent. Cancer Res. 78, 2475–2489
Dellaire, G. et al. (2006) Promyelocytic leukemia nuclear bodies
behave as DNA damage sensors whose response to DNA
double-strand breaks is regulated by NBS1 and the kinases
ATM, Chk2, and ATR. J. Cell Biol. 175, 55–66
Voisset, Edwige et al. (2017) Pml nuclear body disruption cooperates in APL pathogenesis and impairs DNA damage repair
pathways in mice. Blood 131, 636–648
Vancurova, M. et al. (2019) PML nuclear bodies are recruited to
persistent DNA damage lesions in an RNF168-53BP1 dependent manner and contribute to DNA repair. DNA Repair 78,
114–127
Lee, J.H. and Paull, T.T. (2005) ATM activation by DNA doublestrand breaks through the Mre11–Rad50–Nbs1 complex.
Science 308, 551–554
Rogakou, E.P. et al. (1998) DNA double-stranded breaks induce histone H2AX phosphorylation on serine 139. J. Biol.
Chem. 273, 5858–5868
Thompson, L.H. (2012) Recognition, signaling, and repair of
DNA double-strand breaks produced by ionizing radiation in
mammalian cells: the molecular choreography. Mutat. Res.
751, 158–246
Bischof, O. et al. (2001) Regulation and localization of the
bloom syndrome protein in response to DNA damage. J. Cell
Biol. 153, 367–380
Yeung, P.L. et al. (2012) Promyelocytic leukemia nuclear
bodies support a late step in DNA double-strand break repair
by homologous recombination. J. Cell. Biochem. 113,
1787–1799
Soo Lee, N. et al. (2016) TRAIP/RNF206 is required for recruitment of RAP80 to sites of DNA damage. Nat. Commun. 7,
10463
González-Prieto, R. et al. (2015) SUMOylation and PARylation
cooperate to recruit and stabilize SLX4 at DNA damage sites.
EMBO Rep. 16, 512–519
Bryan, T.M. et al. (1997) Evidence for an alternative mechanism
for maintaining telomere length in human tumors and tumorderived cell lines. Nat. Med. 3, 1271–1274
Lovejoy, C.A. et al. (2012) Loss of ATRX, genome instability,
and an altered DNA damage response are hallmarks of the
alternative lengthening of telomeres pathway. PLoS Genet. 8,
e1002772
Yeager, T.R. et al. (1999) Telomerase-negative immortalized
human cells contain a novel type of promyelocytic leukemia
(PML) body. Cancer Res. 59, 4175–4179
Osterwald, S. et al. (2015) PML induces compaction, TRF2
depletion and DNA damage signaling at telomeres and promotes their alternative lengthening. J. Cell Sci. 128,
1887–1900
Loe, T.K. et al. (2020) Telomere length heterogeneity in ALT
cells is maintained by PML-dependent localization of the BTR
complex to telomeres. Genes Dev. 34, 650–662
Trends in Cancer, Month 2020, Vol. xx, No. xx
97.
98.
99.
100.
101.
102.
103.
104.
105.
106.
107.
108.
109.
110.
111.
112.
113.
114.
115.
116.
117.
118.
119.
120.
121.
122.
Min, J. et al. (2019) Clustered telomeres in phase-separated
nuclear condensates engage mitotic DNA synthesis through
BLM and RAD52. Genes Dev. 33, 814–827
Sobinoff, A.P. et al. (2017) BLM and SLX4 play opposing roles
in recombination-dependent replication at human telomeres.
EMBO J. 36, 2907–2919
Episkopou, H. et al. (2019) TSPYL5 depletion induces specific
death of ALT cells through USP7-dependent proteasomal degradation of POT1. Mol. Cell 75, 469–482.e6
Wang, H. et al. (2018) CRISPR-mediated programmable 3D
genome positioning and nuclear organization. Cell 175,
1405–1417
Chu, Y. and Yang, X. (2011) SUMO E3 ligase activity of TRIM
proteins. Oncogene 30, 1108–1116
Keown, J.R. et al. (2016) Characterisation of assembly and
ubiquitylation by the RBCC motif of Trim5α. Sci. Rep. 6,
26837–26837
Dawidziak, D.M. et al. (2017) Structure and catalytic activation
of the TRIM23 RING E3 ubiquitin ligase. Proteins 85,
1957–1961
Sanchez, J.G. et al. (2016) Mechanism of TRIM25 catalytic activation in the antiviral RIG-I pathway. Cell Rep. 16, 1315–1325
Voisset, E. et al. (2018) Pml nuclear body disruption cooperates
in APL pathogenesis and impairs DNA damage repair pathways in mice. Blood 131, 636–648
Martens, J.H. et al. (2010) PML–RARalpha/RXR alters the epigenetic landscape in acute promyelocytic leukemia. Cancer
Cell 17, 173–185
Wang, K. et al. (2010) PML/RARalpha targets promoter regions
containing PU.1 consensus and RARE half sites in acute
promyelocytic leukemia. Cancer Cell 17, 186–197
Grignani, F. et al. (1998) Fusion proteins of the retinoic acid
receptor-alpha recruit histone deacetylase in promyelocytic
leukaemia. Nature 391, 815–818
Lin, R.J. et al. (1998) Role of the histone deacetylase complex
in acute promyelocytic leukaemia. Nature 391, 811–814
Villa, R. et al. (2007) Role of the polycomb repressive complex 2
in acute promyelocytic leukemia. Cancer Cell 11, 513–525
Di Croce, L. et al. (2002) Methyltransferase recruitment and
DNA hypermethylation of target promoters by an oncogenic
transcription factor. Science 295, 1079–1082
Wang, Z.Y. and Chen, Z. (2008) Acute promyelocytic leukemia:
from highly fatal to highly curable. Blood 111, 2505–2515
Zhu, H.H. et al. (2018) Oral arsenic plus retinoic acid versus intravenous arsenic plus retinoic acid for non-high-risk acute
promyelocytic leukaemia: a non-inferiority, randomised phase
3 trial. Lancet Oncol. 19, 871–879
Zhu, J. et al. (1999) Retinoic acid induces proteasome-dependent degradation of retinoic acid receptor alpha (RARalpha)
and oncogenic RARalpha fusion proteins. Proc. Natl. Acad.
Sci. U. S. A. 96, 14807–14812
Jeanne, M. et al. (2010) PML/RARA oxidation and arsenic binding
initiate the antileukemia response of As2O3. Cancer Cell 18, 88–98
de The, H. et al. (2017) Acute promyelocytic leukemia: a paradigm for oncoprotein-targeted cure. Cancer Cell 32, 552–560
Goto, E. et al. (2011) Missense mutations in PML–RARA are critical for the lack of responsiveness to arsenic trioxide treatment.
Blood 118, 1600–1609
Dong, S. et al. (1996) Amino-terminal protein-protein interaction
motif (POZ domain) is responsible for activities of the
promyelocytic leukemia zinc finger–retinoic acid receptor α gene
fusion protein. Proc. Natl. Acad. Sci. U. S. A. 93, 3624–3629
Liu, Y. et al. (2006) The tetramer structure of the Nervy homology two domain, NHR2, is critical for AML1/ETO's activity.
Cancer Cell 9, 249–260
Hoogeveen, A.T. et al. (2002) The transcriptional corepressor
MTG16a contains a novel nucleolar targeting sequence deranged in t(16;21)-positive myeloid malignancies. Oncogene
21, 6703–6712
McWhirter, J.R. et al. (1993) A coiled-coil oligomerization
domain of Bcr is essential for the transforming function of
Bcr–Abl oncoproteins. Mol. Cell. Biol. 13, 7587–7595
Peiris, M.N. et al. (2019) Oncogenic fusion protein BCR–FGFR1
requires BCR-mediated oligomerization and chaperonin Hsp90
for activation. Haematologica 105, 1262–1273
Trends in Cancer
123. So, C.W. et al. (2003) Dimerization contributes to oncogenic
activation of MLL chimeras in acute leukemias. Cancer Cell 4,
99–110
124. Fischer, M. et al. (2005) Defining the oncogenic function of the
TEL/AML1 (ETV6/RUNX1) fusion protein in a mouse model.
Oncogene 24, 7579–7591
125. Qiu, J.J. et al. (2011) The reduced and altered activities of PAX5
are linked to the protein-protein interaction motif (coiled-coil
domain) of the PAX5–PML fusion protein in t(9;15)-associated
acute lymphocytic leukemia. Oncogene 30, 967–977
126. Occhionorelli, M. et al. (2011) The self-association coiled-coil
domain of PML is sufficient for the oncogenic conversion of
the retinoic acid receptor (RAR) alpha. Leuk. Res. 25, 814–820
127. Dong, S. et al. (2003) Essential role for the dimerization domain
of NuMA–RARalpha in its oncogenic activities and localization
to NuMA sites within the nucleus. Oncogene 22, 858–868
128. Dong, S. and David, J.T. (2002) Interactions of STAT5b–RARa,
a novel acute promyelocytic leukemia fusion protein, with
retinoic acid receptor and STAT3 signaling pathways. Blood
99, 2637–2646
129. Siegel, P.M. and Muller, W.J. (1996) Mutations affecting conserved cysteine residues within the extracellular domain of
Neu promote receptor dimerization and activation. Proc. Natl.
Acad. Sci. U. S. A. 93, 8878–8883
130. Weiner, D.B. et al. (1989) Linkage of tyrosine kinase activity with
transforming ability of the p185neu oncoprotein. Oncogene 4,
1175–1183
131. Taieb, D. et al. (2008) ArgBP2-dependent signaling regulates
pancreatic cell migration, adhesion, and tumorigenicity. Cancer
Res. 68, 4588–4596
132. Roignot, J. et al. (2014) Oligomerization and phosphorylation
dependent regulation of ArgBP2 adaptive capabilities and associated functions. PLoS One 9, e87130
133. Soda, M. et al. (2007) Identification of the transforming EML4–
ALK fusion gene in non-small-cell lung cancer. Nature 448,
561–566
134. Sasaki, T. et al. (2010) The biology and treatment of EML4-ALK
non-small cell lung cancer. Eur. J. Cancer 46, 1773–1780
135. Richards, M.W. et al. (2015) Microtubule association of EML
proteins and the EML4-ALK variant 3 oncoprotein require an
N-terminal trimerization domain. Biochem. J. 467, 529–536
136. Cooper, C.S. et al. (1984) Molecular cloning of a new
transforming gene from a chemically transformed human cell
line. Nature 311, 29–33
137. Yu, J. et al. (2000) Frequency of TPR–MET rearrangement in
patients with gastric carcinoma and in first-degree relatives.
Cancer 88, 1801–1806
138. Soman, N.R. et al. (1991) The TPR–MET oncogenic rearrangement is present and expressed in human gastric carcinoma
and precursor lesions. Proc. Natl. Acad. Sci. U. S. A. 88,
4892–4896
139. Pal, K. et al. (2017) Structural basis of TPR-mediated oligomerization and activation of oncogenic fusion kinases. Structure
25, 867–877
140. Rodrigues, G.A. and Park, M. (1993) Dimerization mediated
through a leucine zipper activates the oncogenic potential
of the met receptor tyrosine kinase. Mol. Cell. Biol. 13,
6711–6722
141. Wu, Y.M. et al. (2013) Identification of targetable FGFR gene
fusions in diverse cancers. Cancer Discov. 3, 636–647
142. Wang, Z.G. et al. (1998) PML is essential for multiple apoptotic
pathways. Nat. Genet. 20, 266–272
143. Wang, Z.G. et al. (1998) Role of PML in cell growth and the
retinoic acid pathway. Science 279, 1547–1551
144. Salomoni, P. and Pandolfi, P.P. (2002) The role of PML in tumor
suppression. Cell 108, 165–170
145. Zhang, P. et al. (2000) Lack of expression for the suppressor
PML in human small cell lung carcinoma. Int. J. Cancer 85,
599–605
146. Datta, N. et al. (2019) Promyelocytic leukemia (PML) gene
regulation: implication towards curbing oncogenesis. Cell
Death Dis. 10, 656
147. Gurrieri, C. et al. (2004) Loss of the tumor suppressor PML in
human cancers of multiple histologic origins. J. Natl. Cancer
Inst. 96, 269–279
148. Wang, Y.T. et al. (2017) Ubiquitination of tumor suppressor
PML regulates prometastatic and immunosuppressive tumor
microenvironment. J. Clin. Invest. 127, 2982–2997
149. Ito, K. et al. (2008) PML targeting eradicates quiescent
leukaemia-initiating cells. Nature 453, 1072–1078
150. Ito, K. et al. (2012) A PML-PPAR-delta pathway for fatty acid
oxidation regulates hematopoietic stem cell maintenance.
Nat. Med. 18, 1350–1358
151. Amodeo, V. et al. (2017) A PML/Slit axis controls physiological
cell migration and cancer invasion in the CNS. Cell Rep. 20,
411–426
152. Carracedo, A. et al. (2012) A metabolic prosurvival role for PML
in breast cancer. J. Clin. Invest. 122, 3088–3100
153. Ponente, M. et al. (2017) PML promotes metastasis of triplenegative breast cancer through transcriptional regulation of
HIF1A target genes. JCI Insight 2, e87380
154. Arreal, L. et al. (2020) Targeting PML in triple negative breast
cancer elicits growth suppression and senescence. Cell
Death Differ. 27, 1186–1199
155. Iwanami, A. et al. (2013) PML mediates glioblastoma resistance
to mammalian target of rapamycin (mTOR)-targeted therapies.
Proc. Natl. Acad. Sci. U. S. A. 110, 4339–4344
156. Zhang, X. et al. (2015) Promyelocytic leukemia protein induces
arsenic trioxide resistance through regulation of aldehyde dehydrogenase 3 family member A1 in hepatocellular carcinoma.
Cancer Lett. 366, 112–122
157. Gentric, G. et al. (2019) PML-regulated mitochondrial metabolism enhances chemosensitivity in human ovarian cancers. Cell
Metab. 29, 156–173
158. Yang, B. et al. (2017) Inhibition of protein kinase CK2 sensitizes
non-small cell lung cancer cells to cisplatin via upregulation of
PML. Mol. Cell. Biochem. 436, 87–97
159. Swayden, M. et al. (2019) PML hyposumoylation is responsible
for the resistance of pancreatic cancer. FASEB J. 33,
12447–12463
160. Cheng, X. et al. (2013) Ablation of promyelocytic leukemia
protein (PML) re-patterns energy balance and protects mice
from obesity induced by a Western diet. J. Biol. Chem. 288,
29746–29759
161. Kuroki, M. et al. (2013) PML tumor suppressor protein is required for HCV production. Biochem. Biophys. Res. Commun.
430, 592–597
162. Li, K. et al. (2017) TRIB3 promotes APL progression through
stabilization of the oncoprotein PML–RARalpha and inhibition
of p53-mediated senescence. Cancer Cell 31, 697–710
163. Lee, J. et al. (2012) Overexpression of IFITM1 has clinicopathologic effects on gastric cancer and is regulated by an epigenetic mechanism. Am. J. Pathol. 181, 43–52
164. Yu, F. et al. (2015) IFITM1 promotes the metastasis of human
colorectal cancer via CAV-1. Cancer Lett. 368, 135–143
165. Andreu, P. et al. (2006) Identification of the IFITM family as a
new molecular marker in human colorectal tumors. Cancer
Res. 66, 1949–1955
166. Han, J.H. et al. (2011) IFITM6 expression is increased in macrophages of tumor-bearing mice. Oncol. Rep. 25, 531–536
167. Ishibashi, T. et al. (2018) Identification of MS4A3 as a reliable
marker for early myeloid differentiation in human hematopoiesis.
Biochem. Biophys. Res. Commun. 495, 2338–2343
168. Jin, W. et al. (2013) AML1–ETO targets and suppresses
cathepsin G, a serine protease, which is able to degrade
AML1–ETO in t(8;21) acute myeloid leukemia. Oncogene 32,
1978–1987
169. Santofimia-Castaño, P. et al. (2019) Targeting the stressinduced protein NUPR1 to treat pancreatic adenocarcinoma.
Cells 8, E1453
170. Chen, Y.L. et al. (2019) Interferon-stimulated gene 15 modulates cell migration by interacting with Rac1 and contributes
to lymph node metastasis of oral squamous cell carcinoma
cells. Oncogene 38, 4480–4495
171. Chen, J. et al. (2019) Type I IFN protects cancer cells from
CD8+ T cell-mediated cytotoxicity after radiation. J. Clin. Invest.
129, 4224–4238
172. Palmer, D.C. et al. (2015) Cish actively silences TCR signaling in
CD8+ T cells to maintain tumor tolerance. J. Exp. Med. 212,
2095–2113
Trends in Cancer, Month 2020, Vol. xx, No. xx
17
Trends in Cancer
173. Karlstetter, M. et al. (2010) The novel activated microglia/
macrophage WAP domain protein, AMWAP, acts as a counterregulator of proinflammatory response. J. Immunol. 185, 3379–3390
174. Weber, C. et al. (2008) The multifaceted contributions of leukocyte subsets to atherosclerosis: lessons from mouse models.
Nat. Rev. Immunol. 8, 802–815
175. Lande, R. et al. (2019) CXCL4 assembles DNA into liquid crystalline complexes to amplify TLR9-mediated interferon-alpha
production in systemic sclerosis. Nat. Commun. 10, 1731
176. Mihelic, M. et al. (2006) Mouse stefins A1 and A2 (Stfa1 and Stfa2)
differentiate between papain-like endo- and exopeptidases. FEBS
Lett. 580, 4195–4199
177. Roper, R.J. et al. (2003) Aod1 controlling day 3 thymectomyinduced autoimmune ovarian dysgenesis in mice encompasses two linked quantitative trait loci with opposing allelic
effects on disease susceptibility. J. Immunol. 170, 5886–5891
178. Runck, A.M. et al. (2009) Evolution of duplicated beta-globin
genes and the structural basis of hemoglobin isoform differentiation in Mus. Mol. Biol. Evol. 26, 2521–2532
18
Trends in Cancer, Month 2020, Vol. xx, No. xx
179. Kumar, R. et al. (2010) Functional conservation of Mei4 for
meiotic DNA double-strand break formation from yeasts to
mice. Genes Dev. 24, 1266–1280
180. Zhang, P. et al. (2000) Lack of expression for the suppressor
PML in human small cell lung carcinoma. Int. J. Cancer 85,
599–605
181. Crowder, C. et al. (2005) PML mediates IFN-alpha-induced
apoptosis in myeloma by regulating TRAIL induction. Blood
105, 1280–1287
182. Gong, P. et al. (2019) Telomere maintenance-associated PML
is a potential specific therapeutic target of human colorectal
cancer. Transl. Oncol. 12, 1164–1176
183. Guion, L. et al. (2019) PML nuclear body-residing proteins
sequentially associate with HPV genome after infectious
nuclear delivery. PLoS Pathog. 15, e1007590
184. Cohen, C. et al. (2018) Promyelocytic leukemia (PML) nuclear
bodies (NBs) induce latent/quiescent HSV-1 genomes
chromatinization through a PML NB/histone H3.3/H3.3
chaperone axis. PLoS Pathog. 14, e1007313