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Blood First Edition Paper, prepublished online January 9, 2015; DOI 10.1182/blood-2014-10-569616
Ribosomopathies and the paradox of cellular hypo- to hyperproliferation
Kim De Keersmaecker 1,2, Sergey O. Sulima 1,2 and Jonathan D. Dinman 3
1 Department of Oncology, KU Leuven, Leuven, Belgium
2 Center for the Biology of Disease, VIB, Leuven, Belgium
3 Department of Cell Biology and Molecular Genetics, University of Maryland, College Park
MD, USA
CORRESPONDENCE
Kim De Keersmaecker, Campus Gasthuisberg O&N4, box 602, Herestraat 49, 3000 Leuven.
[email protected]
Jonathan D. Dinman, Microbiology Building #231, Department of Cell Biology and Molecular
Genetics, University of Maryland, College Park MD 20742 USA. [email protected]
1
Copyright © 2015 American Society of Hematology
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ABSTRACT
Ribosomopathies are largely congenital diseases linked to defects in ribosomal proteins or
biogenesis factors. Some of these disorders are characterized by hypoproliferative
phenotypes such as bone marrow failure and anemia early in life, followed by elevated cancer
risks later in life. This transition from hypo- to hyperproliferation presents an intriguing
paradox in the field of hematology known as ‘Dameshek’s riddle.’ Recent cancer sequencing
studies also revealed somatically acquired mutations and deletions in ribosomal proteins in Tcell acute lymphoblastic leukemia (T-ALL) and solid tumors, further extending the list of
ribosomopathies and strengthening the association between ribosomal defects and
oncogenesis. In this perspective, we summarize and comment on recent findings in the field
of ribosomopathies. We explain how ribosomopathies may provide clues to help explain
Dameshek’s paradox and highlight some of the open questions and challenges in the field.
2
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INTRODUCTION
Ribosomopathies are a collection of disorders of ribosome dysfunction characterized by a
defect in ribosome biogenesis, typically due to a mutation in a ribosomal protein or biogenesis
factor. They are rare diseases, with the most frequent having incidences in the range of 1 in
50 000 to 1 in 200 000 live births. These include Diamond-Blackfan Anemia (DBA) and 5qsyndrome that are associated with mutations in ribosomal proteins, as well as diseases linked
to defects in ribosome biogenesis factors such as Schwachman-Diamond syndrome (SDS)
and Treacher Collins syndrome (TCS). An example of a rarer ribosomopathy is X-linked
dyskeratosis congenita. All of these diseases are characterized by distinct clinical phenotypes
and patients present with one or several of a wide variety of developmental abnormalities
including
hematopoietic
defects
(e.g.
anemia
and
other
cytopenias),
craniofacial
malformations, short stature, mental and motor retardation. Although diverse, these
phenotypes can all be categorized as cellular hypoproliferative defects. Intriguingly, some
ribosomopathy patients are also at increased risk of developing leukemias and solid tumors,
i.e.
hyperproliferative cellular defects.1,2,3
For example: DBA is characterized
by
hypoproliferation phenotypes including macrocytic anemia, short stature, craniofacial defects
and thumb abnormalities beginning early in life. In addition, these patients have been
reported to have a 5-fold higher incidence of cancers, with the highest predisposition to colon
cancer (36-fold higher incidence than in the general population), osteosarcoma (33-fold
higher) and acute myeloid leukemia (28-fold higher).1 Although these associations with
elevated cancer risks have been described in DBA, it is important to remark that this is a rare
disease and that the number of cancer cases studied remains limited. Further studies
demonstrating a causal link between ribosomal defects and elevated cancer risks in DBA are
needed. Additionally, it is important to note that elevated cancer risks have not been
demonstrated in all ribosomopathies, e.g. TCS has not been linked to any higher cancer
predisposition.
It is not our aim here to give an extensive overview of ribosomopathies or an in depth
description of the exact clinical manifestations of the different diseases. Therefore, we refer to
excellent reviews written by others.
4,5,6
It is important to point out that ribosomopathies
represent only a subset of congenital bone marrow failure syndromes: marrow failure and
myelodysplasia with associated risk for transformation can also be caused by other classes of
congenital and non-congenital defects such as mutations in genes involved in DNA repair
7
8
9
(mutations in Fanconi anemia pathway), telomere regulation, epigenetics and splicing .
These are however not the subjects of this perspective.
In this perspective, we summarize and comment on recent findings in the field of
ribosomopathies. To begin, we highlight the rapid expansion of the ribosomopathy field due to
the discovery of somatic mutations in ribosomal proteins in T-cell acute lymphoblastic
leukemia (T-ALL) and other cancer samples. Next, we summarize the state-of-the-art of the
3
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molecular biology underlying the hypo- and hyperproliferative phenotypes in ribosomopathies
and provide a model that may partially explain the transition from one to the other
(Dameshek’s riddle). Finally, we discuss some of the open questions and future perspectives
in the field.
'TO BE' OR 'NOT TO BE' A RIBOSOMOPATHY: TOWARDS A DEFINITION
The birth of the field of ribosomopathies dates back to 1999, when Draptchinskaia and
colleagues described mutations in the ribosomal protein coding gene RPS19/eS19 (please
note that the second nomenclature refers to the universal ribosomal protein nomenclature
which was recently introduced to conform to atomic resolution ribosome structures from all
three domains of life)10 in DBA.11 Since then, the list of ribosomopathies has continued to
grow. One example is the recent discovery of congenital mutations in ribosomal protein SA
(RPSA/uS2) in patients with isolated congenital asplenia.
12
Another important expansion of
the list of ribosomopathies comes from the recent application of unbiased next generation
sequencing based mutation screening to cancer samples. Whereas previously all
ribosomopathies (with the exception of the 5q- syndrome, linked to somatic loss of the
RPS14/uS14 gene) have been associated with congenital genetic defects, genome wide
sequencing efforts of cancer samples revealed that some of the genes associated with such
congenital defects in ribosomopathies can also be targets of somatic mutation in cancers. For
example, we recently identified inactivating mutations in the gene encoding ribosomal protein
L5 (RPL5/uL18) in patients with T-ALL, some of which are identical to mutations described in
DBA patients.13 Rare somatic mutations in T-ALL patients were also identified in RPL11/uL5,
another gene that is affected in DBA.14 Interestingly, somatic defects in ribosomal proteins
that have not been implicated in congenital ribosomopathies have now also been identified in
T-ALL, gastric and ovarian cancer. These include somatic mutations in the RPL10/uL16 and
RPL22/eL22 genes.13,15,16,17 Consistent with the observation that patients with congenital
ribosomopathies are predisposed to develop various tumor types, the presence of somatic
ribosome defects is emerging as a common occurrence in cancers.18 In the near future,
completion of ongoing cancer sequencing projects will deepen our understanding of the
spectrum of ribosomal mutations in cancer and may also identify ribosome biogenesis factors
implicated in carcinogenesis.
The discovery of somatic ribosome defects in cancer samples calls into question the current
definition of ‘ribosomopathy’. Should the definition be limited to diseases and syndromes
involving congenital mutations in ribosomal protein or biogenesis factor genes only, or should
it be broadened to include somatically acquired mutations as well? Precedent for the latter
definition may be found in 5q- syndrome. The observations that not all diseases typically
accepted as ribosomopathies are associated with elevated cancer risks and that clinical
4
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hypoproliferative phenotypes have not been noted in cancers with somatic ribosome
mutations suggests that the ‘ribosomopathies’ should be broadly defined. However, to err on
the side of caution, we do think that a causal link between the ribosome defect and
associated disease should have been demonstrated before calling a disease a
ribosomopathy. Therefore, we propose a conservative definition of ribosomopathies as ‘any
disease associated with a mutation in a ribosomal protein or biogenesis factor impairing
ribosome biogenesis in which a defect in ribosome biogenesis or function can be clearly
linked to disease causality’. It is not clear at this point if a disease like cartilage hair
hypoplasia falls under this definition. So far there has been no clear demonstration of a role
for RNase MRP, the gene affected in cartilage hair hypoplasia, in ribosome biogenesis in
humans. Moreover, it is currently unclear whether ribosome dysfunction is the cellular basis
for the disorder. This definition also leaves ribosome mutant cancers in a gray zone: although
loss of an RPL22/eL22 allele is able to accelerate tumor formation in a mouse model of T-cell
leukemia,15 the causal role of other somatic ribosome mutations described in cancer remains
to be shown.
It is worth noting that somatic mutations in ribosomal proteins and biogenesis factors have
only been described in a limited set of cancer samples to date. However, several cancer
types are characterized by recurrent large deletions in which no tumor suppressor gene has
yet been identified and which contain a ribosomal protein gene that is considered intrinsically
‘uninteresting.’ Our recent findings suggest that defects in ribosomal proteins and other
synthesis factors should not be overlooked in cancer genotypes. Additionally, it has been
clearly established by many research groups that protein synthesis appears deregulated in
the majority, if not all, cancer samples. This is not surprising: this process plays such a central
role in the cell that the signaling cascades and transcriptional regulators that are prominently
altered in cancer also (de)regulate translation.
Indeed, aberrations
affecting the
PI3K/AKT/mTOR pathway, the tumor suppressor protein p53 (TP53) pathway and the MYC
transcription factor in cancer also impact cellular protein translation by deregulating
expression of components of the translation machinery and by influencing the set of mRNAs
which are most efficiently translated in the cell.19,20 However, whether altered translation in
these instances is the cause of or consequence of cellular transformation is not clear.
Therefore, we think it is not appropriate at this point to call such tumors ribosomopathies.
HOW RIBOSOMOPATHIES CAN OFFER NEW INSIGHTS INTO DAMESHEK’S RIDDLE
In a 1967 editorial, the founding editor-in-chief of Blood, William Dameshek, posed the
following riddle: 'What do aplastic anemia, paroxysmal nocturnal hemoglobinuria (PNH) and
'hypoplastic' leukemia have in common?'.21 Here, Dameshek described the intriguing paradox
in which patients who initially develop a hypoproliferative disease such as aplastic anemia
tend to be at higher risk of hyperproliferative diseases such as PNH (clonal expansion of red
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cells) or acute leukemia (clonal expansion of white cells) later in life. Although not explicitly
described by Dameshek, this observation of a class of diseases characterized in the early
stages by a hypoproliferative disorder followed by the propensity to develop into a
hyperproliferative disease fits the clinical presentation of certain ribosomopathies. As such,
Dameshek’s riddle may be more broadly applicable than initially postulated.
The challenge is to explain this paradox. Dameshek proposed that a sufficiently severe insult
to the marrow - whether chemical, ionizing radiation, viral or by a congenital defect - may
result in a variable degree of injury with a variable degree of hypoplasia. In some cases,
abnormal clones of abnormal leukocytes (hypoplastic leukemia) or red cells (PNH) could
conceivably arise during the process of repair.
21
In other words, Dameshek proposed that an
initial insult first results in hypoproliferative disease, and that something involved in the
process of its repair provides a subset of cells with the capacity to proliferate excessively.
This idea was conceived in 1967, before the molecular genetics era. Remarkably, his model
remains consistent with the models that are currently being proposed to explain Dameshek’s
riddle. The differences lie in the depth of our understanding of the molecular nature of the
'initial insult', the identities of the signaling cascades that lead to impaired proliferation, and
the nature of the molecular 'repair processes' that may underlie the transition to
hyperproliferation.
As discussed above, the initial insult occurring in ribosomopathies are defects in ribosomal
protein genes and biogenesis factors. Ribosome biogenesis is a complex multistage
process.
22
Given the central role of the ribosome in the genetic program, there is strong
pressure in cells to identify and remove malfunctioning ribosomes before they are released
into the cytoplasmic pool of actively translating ribosomes. It is becoming clear that this
process involves quality control mechanisms that operate at each step of the process.23,24
This has two consequences. The first is that cells may not produce enough functional
ribosomes to support their metabolic demands. This is particularly germane to hematopoietic
cells, whose normally high proliferative rates require large amounts of ribosomes. This alone
may account for cellular hypoproliferation. In addition, too few functional ribosomes due to
insufficient quantities of one or more ribosomal proteins may also result in the release of
excess free ribosomal proteins into the cytoplasm. This is a molecular stress signal. The most
well-documented research in this area focuses on cytoplasmic release of RPL5/uL18 and
RPL11/uL5. These have been shown to bind to and inhibit the murine double minute 2 protein
(MDM2, or HDM2 in humans), a ubiquitin ligase that directs degradation of the TP53 protein.
HDM2 inhibition results in TP53 stabilization, initiating a series of cellular signaling cascades
leading to cell cycle arrest and apoptosis, adding to cellular hypoproliferation.25,26,27,28,29,30 This
research only represents the tip of the iceberg: TP53 independent cell cycle arrest and
apoptosis mechanisms have been described that may also contribute to the ribosomopathicstress induced hypoproliferation.
31,32,33,34
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Although the human ribosome consists of 81 ribosomal proteins, only a fraction of these have
been described as mutated or deleted in ribosomopathies. Similarly, only a restricted set of
biogenesis factors have been implicated in ribosomopathies to date.
4,5
This is most likely
explained by the fact that mutation or deletion of many ribosomal proteins and biogenesis
factors would be incompatible with cell survival and affected cells would thus not live long
enough to produce the ribosomopathic phenotype. Indeed, the ribosomal proteins currently
implicated in ribosomopathies encode proteins located on the cytoplasmic/solvent-accessible
surfaces of the ribosome.35 None of these proteins stabilize interdomain rRNA interactions,
nor are they located in regions of the ribosome that directly mediate mRNA decoding or
peptidyl transfer, leaving ribosomopathic ribosomes functional enough to support viability.
Two
typical
trans-acting
ribosomopathogenic
factors,
Shwachman–Bodian–Diamond
syndrome protein (SBDS) and dyskerin (DKC1), are also consistent with this idea: SBDS is
involved in the late, cytoplasmic quality control of pre-60S subunits,24 and DKC1 catalyzes
pseudouridylation of rRNA. Although rRNA modifications occur early during rRNA
transcription, these are thought to merely “fine-tune” ribosome structure rather than playing
central roles in domain folding.36,37,38
The next issue concerns the nature of the 'repair process' in Dameshek’s model. Not
surprisingly, this is less well understood as it is more complex. To approach this, we have
turned to molecular evolutionary theory. As described above, the original mutation results in
too few cells available to perform their physiological function, e.g. production of red blood
cells. From an evolutionary standpoint, this places pressure on the dwindling population of
hematopoietic stem cells, selecting for mutations that enable cells to produce enough
ribosomes to meet their protein synthetic requirements. One such class of mutants are those
that repair the original defect (revertants). A second class, referred to as second site
suppressors, are mutations that either inactivate or bypass the ribosome biogenesis quality
control apparatus. Cells harboring this class of mutations would produce enough ribosomes
to satisfy their translational requirements, enabling them to out-compete those having only the
original mutation. While this solves the hypoproliferation problem, the tradeoff is that these
cells must utilize defective ribosomes. Emerging research indicates that these ribosomes
have specific defects in translational fidelity, i.e. their ability to faithfully translate the genetic
code. Indeed, our laboratories have begun to identify a causal chain of events detailing how
ribosomopathy associated defects such as RPL10/uL16 R98S or Cbf5p-D95A (a catalytically
impaired mutant of Cbf5p, the yeast homologue of DKC1) cause subtle changes in ribosome
structure that alter the basic biochemistry of mutant ribosomes, and how this in turn affects
specific aspects of translational fidelity, altering the expression of specific sets of genes.35,38
For RPL10/uL16 R98S, we also showed that these changes in gene expression confer new
stresses on this population of cells, hastening the selection for additional compensatory
35
mutations that eventually result in cellular immortalization, i.e. hyperproliferation.
7
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classic ‘deal with the devil’: the process that initially enables cells to fulfill their physiological
function eventually leads to their uncontrolled growth and cancer.
The current challenge is to identify the critical second site suppressors. Once identified,
rational strategies can be designed to reverse their effects. The ideal samples would be
tumors collected from patients that developed a ribosome defect associated malignancy.
Such patient samples are however scarce because, fortunately, not all patients develop
malignancies. Moreover, cancer samples are often characterized by genetic instability and
accumulation of defects, making it difficult to pinpoint the exact nature of the original
hypoproliferation suppressor mutation. This is where the molecular genetics of model
organisms becomes a powerful tool. Recent work from our laboratories provides insight into
the molecular nature of the 'repair process'. This began with identification of a recurrent
arginine to serine mutation (R98S) in ribosomal protein RPL10/uL16 in T-ALL patient cells.
Intriguingly, while T-ALL represents a hyperproliferative disease, introduction of this mutation
into yeast and mammalian cells impairs ribosome biogenesis and cellular proliferation
causing the hypoproliferative phenotype.13 In depth analysis of the RPL10/uL16 R98S mutant
using the yeast genetic model revealed that this mutation does not completely inhibit
ribosome biogenesis: this is why they are alive, albeit barely. Importantly, allowing cells to
grow over many generations selected for a population of cells with normal growth rates.
Genetic analysis revealed that this was due to acquisition of a compensatory mutation in a
ribosome biogenesis factor that bypassed a critical quality control checkpoint. Importantly,
while this second site mutation rescued the hypoproliferative defect, it did not correct the
underlying structural, biochemical and translational fidelity defects and altered gene
expression profiles conferred by the original RPL10/uL16 R98S mutation (Figure 1A, B).35
While we have not been able to identify analogous mutations in biogenesis factors in
RPL10/uL16 R98S positive T-ALL samples, this may be due to the paucity of knowledge
pertaining to human biogenesis factors, i.e. mammalian ribosome biogenesis factors are still
poorly defined. Additionally, yeast and human cells are sufficiently different that mutations in
alternative classes of genes may be required to rescue human cell proliferation defects. For
example, human cells may mutate components of the TP53 pathway or of the other pathways
that initiate hypoproliferation upon ribosome biogenesis-induced stress (Figure 1C). It would
be highly interesting to perform polysome profiling on non-cancerous versus cancerous tissue
from patients with a congenital ribosome defect to determine whether a compensatory
mutation was acquired that corrects the biogenesis defect (Figure 1B) or whether the
biogenesis defect is still present, as predicted by the model shown in Figure 1C.
Zebrafish are also becoming an attractive model to study ribosome mutation associated
cancers. Seventeen zebrafish lines have been described harboring heterozygous inactivation
of different ribosomal protein genes that are predisposed to develop malignancies. These
tumors have much in common with those observed in Tp53 null zebrafish, and tumors
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induced by ribosomal protein haploinsufficiency showed a specific translation defect impairing
Tp53 protein production.39 Unfortunately, a hypoproliferative phenotype has not been
described in these fish, and thus it remains unclear whether or not defective Tp53 translation
can actually cause a switch from a hypo- to a hyperproliferative phenotype in this model
system.
A mouse model on RPL22/eL22 haploinsufficiency supports the idea that a
ribosomal protein defect may contribute to a hyperproliferative phenotype provided that
additional mutations are present. RPL22/eL22 has been described as a target for
heterozygous somatic mutations and deletions in T-ALL and in microsatellite instabilitypositive gastric and endometrial cancer.15,40,17 Whereas Rpl22/eL22
+/-
mice do not develop
any malignancies within 25 weeks, crossing of these mice to a strain with T-cell specific
expression of myristoylated Akt2 (MyrAkt2) accelerates the latency of T-cell lymphoma
development from 19 weeks (MyrAkt2- Rpl22/eL22+/+) to 11 weeks (MyrAkt2- Rpl22/eL22+/).15 Although very interesting, these data still do not identify the nature of the extra mutations
that human cancer cells acquire to be transformed in the context of a ribosomal defect. It is
also worth remarking that although loss of 1 copy of Rpl22/eL22 is sufficient to accelerate Tcell lymphoma development in a MyrAkt2 background, loss of both Rpl22/eL22 copies is
needed to observe a hyperproliferative phenotype of arrested development of alphabetalineage T cells at the beta-selection checkpoint.15,41
FUTURE PERSPECTIVES AND CONCLUSIONS
A long list of genes associated with ribosomopathies has been generated over the past three
decades. However, it is clear that we are still far from the goal of a complete understanding of
the pathogenesis of ribosomopathies. Essential information regarding the cellular changes
associated with ribosomal mutations remains to be discovered. While mRNA expression
studies may provide certain clues,42,43,44,45 given that protein translation is the central function
of ribosomes, it may be essential to complement these studies by a detailed analysis of the
effects on protein production. This necessity is illustrated by the recent finding that in a
substantial fraction of DBA cases, one consequence of the ribosomal protein mutations is
failure of translation of the transcription factor GATA-1, an essential factor for development of
erythropoiesis beyond the CFU-E stage. This may be because the long form of GATA-1 is
difficult to translate and is impaired in DBA cells.
46
These translational defects of GATA-1
were found because of the rarity of GATA-1 mutations in DBA. However, additional
translation defects in DBA and other ribosomopathies have probably not been discovered
because of a lack of thorough comparative proteomic studies of normal versus
ribosomopathic cells. Unfortunately, this is a classic example of a problem waiting for a
technological advance; proteomics technologies are still evolving and analyzing an entire
proteome of human cells is not yet within reach of research labs. At this juncture, sequencing
of polysome associated RNA undergoing translation is an option.
47,48,49
The best
approximation at this point is ribosome profiling technology, which allows not only
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identification of ribosome protected (= translated) mRNA fragments but also analysis of
alternative start codon usage, read-through beyond stop codons and of translational
kinetics.
50,51
Additionally, although the need for cooperating mutations appears to be clear,
questions remain regarding the nature of these mutations, the moment when they are
acquired and the amount required to stimulate hyperproliferation. One attractive possibility
accounting for the varying penetrance of cancers in different ribosomopathy patients may lie
in their genetic backgrounds, i.e. cooperating mutations may be inherited as allelic variants
that are normally maintained in the population.
Yet another intriguing paradox regarding ribosomopathies is the issue of phenotypic tissue
specificity: why are such a wide spectrum of clinical presentations with typical tissue-specific
pathologies observed for each disease, despite the fact that they all share a common defect
in the same biochemical process? While patients with congenital ribosomopathies are born
with the same ribosome defect in each cell of their body, not all tissues are affected and only
5
particular disease symptoms are developed. Interestingly, although mutations in several
ribosomal proteins and biogenesis factors give rise to anemia in different ribosomopathies,
each disease also exhibits additional unique features. Even within the same ribosomopathy,
mutations in different ribosomal protein genes promote different types of birth defects. For
instance, most patients with RPL5/uL18 mutations have a cleft palate, whereas most
individuals with RPL11/uL5 mutations do not have any craniofacial defects.52 As such,
patients with genetic disorders that are linked to mutations in ribosomal proteins show
remarkably specific phenotypes, suggesting that ribosomal proteins have unique functions in
different tissues. Dissecting the molecular and biochemical defects of different types of
mutant ribosomes can contribute to the exciting emerging field of ‘specialized ribosomes’ –
ribosomes whose specificity may be controlled and fine-tuned by tissue-specific and
developmentally regulated signals. Alternatively, essential tissue-specific roles of ribosomal
proteins outside of the ribosome (extra-ribosomal functions) may explain the tissue-specific
phenotypes. Indeed, there is a growing body of evidence that ribosomal proteins do not only
function in translation and that they can also regulate transcription and enzyme activity in the
cell.53
In conclusion, many potential explanations for cellular transformation exist and are important
subjects for investigation. We speculate that the ribosomal protein and biogenesis mutants in
ribosomopathies allow the ribosome to become mature enough to support some degree of
translation, yet still cause sufficient perturbations of ribosomal function to effect the changes
in gene expression associated with ribosomopathic phenotypes. Indeed, we showed that
yeast cells expressing a T-ALL associated RPL10/uL16 R98S mutant or a Cbf5p-D95A
mutant promote specific defects in translation fidelity.35,38 Based on our work on RPL10/uL16
R98S,
35
we also hypothesize that compensatory mutations might be likely drivers of
transformation, and are hence particularly important because they allow bypass of the cellular
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proliferation defects due to defective ribosome biogenesis. One class of compensatory
mutations comprises mutant biogenesis factors which suppress the assembly but not the
functional defects of mutant ribosomes. This leads to increased cellular utilization of defective
ribosomes with altered fidelity. Additional experimental work is needed to validate this model
in other systems and for other ribosomal defects. Moreover, while bypassing the ribosomal
assembly quality control through mutated biogenesis factors may provide one window to
oncogenesis, it is likely that other classes of oncogenic secondary mutations exist. Indeed it is
becoming clear that cooperating secondary mutations/suppressors are frequently required for
disease development.54 Transformation merely represents an endpoint that is likely made
more accessible by evolutionary selection for secondary mutations in a variety of cellular
pathways. Determining the nature of the pathways and the mutations is an exciting and
promising field for investigation.
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ACKOWLEDGEMENTS
KDK receives a postdoctoral fellowship of FWO Vlaanderen. SOS is recipient of an EMBO
long-term postdoctoral fellowship. This work was partially supported by a grant from the
National Institutes of Health to JDD (R01 HL119438) and by an FWO grant (G.0840.13), a
Stichting Tegen Kanker (F25) and an ERC starting grant (GA 334946) to KDK.
AUTHORSHIP CONTRIBUTIONS
KDK, SOS and JDD wrote and edited the manuscript.
DISCLOSURE OF CONFLICTS OF INTEREST
The authors declare no competing financial interests
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FIGURE LEGENDS
Figure 1. Model explaining transition from hypo- to hyperproliferation phenotypes in
ribosomopathies. (A) In the initial phase of the disease, a mutation in a ribosomal protein or
ribosome biogenesis factor (symbolized by the red star on the 60S subunit) impairs proper
ribosome biogenesis, resulting in lower concentrations of assembled ribosomes. This
ribosome biogenesis defect impairs proper proliferation of the cells by activating the TP53
pathway and/or by TP53 independent mechanisms. At this stage, functional ribosomes are
still assembled to a certain extent. These ribosomes are however intrinsically defective and
may induce translational changes/shifts in the cells. (B + C) The impaired proliferation
imposes strong pressure on cell populations, selecting for cells that acquire a compensatory
mutation rescuing the impaired proliferation. The nature of this compensatory mutation is
currently unclear. Cells may acquire a mutation in a biogenesis factor rescuing the biogenesis
defect (B). Alternatively, the signaling pathways inducing the proliferation impairment upon a
biogenesis defect (TP53 or other) may be crippled by a compensatory mutation (C). In both
scenarios, after acquiring the compensatory mutation, defective ribosomes would still be
formed that alter the translational capacity/fidelity leading to the cell obtaining a clonal
15
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advantage over other cells. However, these ribosomes are intrinsically defective, leading to
altered gene expression programs. More speculative parts in the figure are indicated by
dashed arrows.
16
Figure 1
A
HYPOPROLIFERATIVE PHASE
Fewer assembled ribosomes
60S
Impaired
proliferation
Biogenesis
defect
TP53 activation
TP53 independent mechanisms
40S
AAAAA
Defective ribosomes
?
Translational changes
Cellular advantage
B
HYPERPROLIFERATIVE PHASE
Assembled ribosomes
60S
Compensatory
Mutation in a
Biogenesis Factor
AAAAA
40S
AAAAA
Defective ribosomes
?
Translational changes
Cellular advantage
C
HYPERPROLIFERATIVE PHASE
Fewer assembled ribosomes
60S
Normal/ Hyperproliferation
Compensatory mutation
in TP53 or other
pathway
Biogenesis
defect
40S
AAAAA
Defective ribosomes
?
Translational changes
Cellular advantage
From www.bloodjournal.org by guest on June 17, 2017. For personal use only.
Prepublished online January 9, 2015;
doi:10.1182/blood-2014-10-569616
Ribosomopathies and the paradox of cellular hypo- to hyperproliferation
Kim De Keersmaecker, Sergey O. Sulima and Jonathan D. Dinman
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