Download A novel BIM deletion polymorphism: implications and

−臨
床
血
液−
The 75th Annual Meeting of
the Japanese Society of Hematology
Myeloid neoplasms：CML, MPN, MDS, and others
EL-21 Topics
A novel BIM deletion polymorphism:
implications and lessons for cancer targeted therapies
Sheila SOH 1,
S. Tiong ONG 1, 2, 3, 4
Key words : Genetic polymorphism, Targeted therapy, Response heterogeneity, Drug resistance
are functionally important, understanding their mecha-
Introduction
Molecularly targeted therapy has revolutionized cancer
therapy, and resulted in consistently high response rates,
nism of action may also provide novel therapeutic
approaches to prevent and/or treat clinical resistance.
Toward this end, we outline our recent discovery of a
often associated with improvements in progression free
common polymorphism in the BIM gene that accounts for
survival (PFS) as well as improved overall survival (OS)1).
heterogeneous responses in at least two human cancers,
These advances have benefited many patients suffering
chronic myeloid leukemia (CML) and epidermal growth
from cancers previously considered to be highly therapy
factor receptor-mutated non-small-cell lung cancer (EGFR
2, 3)
resistant
. Such advances are based on the ability to
NSCLC), and the lessons we have learned from it4).
identify the molecular drivers of each cancer, and
With over a decade of experience in many such cancer
The BIM deletion polymorphism and intrinsic
resistance to targeted therapies
models, we have begun to appreciate that a major issue
To identify structural variations (SVs) that were
facing the field is the degree of response heterogeneity
associated with tyrosine kinase inhibitor (TKI) resistance
observed across different cancers even when they
in CML patients, we used DNA sequencing of paired-end
molecularly defined and targeted. This heterogeneity
ditags (DNA-PET) to sequence and compare the ge-
encompasses significant variations in depth of response to
nomes of three TKI-resistant patients with those of two
initial therapy, duration of response, and OS. A major
TKI-sensitive patients. From the list of SVs that occurred
challenge will be to understand the basis for tumor and
exclusively in the TKI-resistant patients, one candidate
patient heterogeneity, and to overcome suboptimal
stood out. This SV was a 2.9 kb deletion that occurred in
responses so that all individuals with cancer can enjoy
intron 2 of the BIM (otherwise known as BCL2L11) gene.
optimal responses. Increased knowledge in this area will
This was of tremendous interest to us given the well-
lead to improved biomarkers for predicting resistance,
known role of BIM in mediating TKI-induced apoptosis in
and disease transformation. Further, if these biomarkers
a number of cancers 5). Targeted sequencing of the BIM
specifically target those drivers pharmacologically.
locus revealed that the same deletion was found in all
1
Cancer & Stem Cell Biology Signature Research Programme,
Duke-NUS Graduate Medical School, Singapore
2
Department of Haematology, Singapore General Hospital,
Singapore
3
Department of Medical Oncology, National Cancer Centre,
Singapore
4
Division of Medical Oncology, Department of Medicine, Duke
University Medical Center Durham, NC, USA
（1714）168
three samples, suggesting germline origin. This was
confirmed when we screened a large cohort of normal
individuals and found that it occurred at a frequency of
12.3％ in East Asian populations, but was absent in African
or European populations. Clinically, a retrospective analysis of an East Asian TKI-treated CML cohort revealed an
increased risk for resistant disease as defined by
臨
床
血
液 54：10
European Leukemia Net criteria (OR/2.94, p/0.02, 95％
heterogeneity may be classified as either acquired and
CI/1.17─7.43) in patients with the polymorphism.
somatic, or inherited and germline. Here, it should be
We went on to show that the deletion results in a switch
appreciated that germline variants may also influence the
in splicing patterns to favor the production of exon 3-
likelihood of the acquisition of acquired mutations that
containing BIM isoforms. Because exon 3 and 4 are
confer resistance, as discussed in more detail below.
spliced in a mutually exclusive fashion, exon 3-containing
Examples of acquired mutations are those that directly
isoforms lack the BH3 domain that is found in exon 4 and
mediate resistance to targeted therapies by interfering
is required for pro-apoptotic function. To prove that the
with the binding of the drug to the active site of the target
polymorphism was sufficient to confer resistance to TKIs,
enzyme. These mutations are thought to arise stochasti-
we introduced it into the K562 cell line using zinc finger
cally in a tumor cell subclone, and as might be expected,
nuclease technology. We demonstrated that the increase
have been described to pre-exist the use of the targeted
in exon 3 to exon 4 ratio was recapitulated in the deletion-
drug7). Examples of germline variants that directly
containing clones and that apoptosis was attenuated in a
mediate resistance to targeted therapies are much rarer.
polymorphism dose-dependent manner. Using the same
More commonly, these variants have an indirect effect,
approach, we validated our in vitro findings in another
and usually affect pharmacologic parameters8). These
kinase-driven cancer, EGFR NSCLC, and showed that pa-
include polymorphisms that either modulate drug metabo-
tients with EGFR NSCLC had inferior progression-free
lism or drug import/export, and thereby cause resistance
survival (PFS) of 6.6 vs 11.9 months when compared to
by modulating intracellular drug concentrations. We also
patients without the deletion polymorphism. Notably, we
consider the situation where germline variants may
were able to overcome resistance mediated by the
enhance the likelihood of a tumor acquiring secondary
polymorphism by using ABT-737, a BH3 mimetic6), to
mutations. In the case of the BIM deletion polymorphism,
pharmacologically restore BIM function in our genome-
it is possible that suboptimal doses of TKIs may allow
edited lines as well as primary samples with the deletion.
subclones of tumor cells to survive, proliferate, and
accumulate secondary mutations that themselves confer
Assessing causes of response heterogeneity in
cancer targeted therapies
TKI resistance.
Recent reviews have classified clinical resistance to
Response heterogeneity is a broad term, and can
targeted therapies as being primary or secondary9). The
include the quality of the initial response to targeted
latter are defined as patients who fail to achieve any
therapy, PFS, and OS. In hematologic malignancies,
response to initial therapy, while the former are those who
including CML, the depth of response is routinely
have an initial response but who subsequently relapse or
measured by standard quantitative laboratory tests (e.g.
progress. Frequently, the causes of primary and secon-
quantitative RT-PCR for BCR-ABL1 transcripts), which
dary clinical resistance are attributed to germline and
serve as a useful and objective measure of initial response.
acquired mutations respectively. However, it should be
In solid tumors, molecularly-based quantitative measures
appreciated that this segregation assumes that germline
are more challenging to assess, and in practical terms
mutations confer absolute drug resistance, which may not
responses are usually limited to measuring best tumor
be the case, especially since tumor populations are known
responses by imaging modalities. Accordingly, other
to be genetically heterogeneous10). This concept will be
surrogate measures of response are frequently used such
discussed further below.
as PFS and OS. However, OS especially can be subject to
Study design is also critical to the efficient discovery of
confounding factors since progressing patients are usually
genetic variants mediating response heterogeneity8). First
treated with alternative therapies including cytotoxic
of all, such studies should be sufficiently powered to
chemotherapy and radiotherapy. Thus, when response
detect variants of clinical significance and be independent-
heterogeneity is assessed it should be specific to the
ly validated. Secondly, when using genome-wide ap-
clinical measure being assessed. In the case of EGFR
proaches to identify variants associated with response
NSCLC, one possible objective clinical measure is the best
heterogeneity, it is important to consider the population
response on CT scans.
being studied to enable efficient discovery. As far as
In the broadest sense, the genetic causes for response
possible, the study should include homogenous popula169（1715）
−臨
床
血
液−
tions, and in the ideal situation, use a single molecularly
played by several groups in clearly and convincingly
defined entity, e.g. EGFR-mutated non-small cell lung
demonstrating the critical importance of BIM expression
cancer, treated with a single agent. Further, if the study is
in determining sensitivity to TKIs in CML12, 13), and the
to identify resistance to targeted therapies, then those
second was the availability of several East Asian CML cell
populations should have been treated only with that agent,
lines, one of which (KCL22) was found to harbor the BIM
otherwise confounding factors will likely be introduced
deletion polymorphism and to be intrinsically resistant to
since resistance and/or sensitivity to different therapeutic
TKIs14). Here, it should be noted that the latter are almost
agents is likely to be multifactorial.
exclusively Japanese in origin, and we owe a debt of
gratitude to investigators in the past for their contribution
Discovery of the BIM deletion polymorphism
to our studies.
The impetus for the work that led to the discovery of the
BIM deletion polymorphism was to uncover mechanisms
Lessons from the discovery of the BIM deletion
that mediated intrinsic resistance to ABL1 kinase inhibi-
One of the most important lessons we learnt from the
tors in CML. Prior work had suggested that a significant
discovery of the BIM deletion polymorphism is the
proportion of individuals with clinical resistance may not
potential for relatively common polymorphisms to contrib-
harbor mutations in BCR-ABL1, particularly those in early
ute significantly to clinical outcome in cancer therapies.
stage disease11). Further, studies in such patients indicat-
This is likely to due to the critical importance that BIM
ed that downstream signalling could still be inhibited by
plays in mediating cancer cell death. Indeed, cancer cells
TKIs, yet they experienced suboptimal responses11).
(as well as normal cells) are exquisitely sensitive to BIM
Together, these observations suggested that BCR-ABL1-
levels, such that gene dosage effects are clearly seen in
independent factors could be underlying resistance.
animal models of cancer15). However, the BIM deletion
Accordingly, when selecting CML samples for genomic
polymorphism is not a perfect predictor of resistance,
studies, we deliberately chose material from patients who
since the odds ratios of an individual with the deletion
had overt clinical TKI resistance but did not harbor BCR-
polymorphism being resistant, while robust and clinically
ABL1 kinase domain mutations.
meaningful, were in the range of 2-3-fold. Thus, the
A second feature of our workflow was to include
deletion polymorphism likely works in concert with other
polymorphic variants as genes of interest, particularly
factors, yet to be defined, to determine the ultimate
those that were enriched in the study population, i.e.
outcome of resistance vs sensitivity.
enriched in patients with resistance compared to those
That the BIM deletion polymorphism is restricted to
without. In many cancer genome-wide studies, polymor-
persons of East Asian ancestry is also of interest. While
phic variants are usually filtered out to increase the
some reports have indicated that TKI response rates in
chances of identifying functional variants (such as driver
CML may be inferior in East Asia compared to the West16),
or resistance-conferring mutations) . Such approaches
response rates for TKIs in other cancers including EGFR
would have discarded the BIM deletion polymorphism.
TKIs in EGFR NSCLC are not clearly inferior in the East
A third feature of our work was combining the pipeline
compared to the West17). This suggests that different
of genetic variants of interest with prompt validation in
ethnicities may harbor polymorphic variants of at least
CML samples segregated according to the phenotype of
equivalent effect to that of the BIM deletion. These may of
interest. Thus, because the deletion was almost 3kb in
course reside in the same gene, or affect other genes in
size, PCR primers could be designed to efficiently detect
the same or similar pathways. Further, these polymorphic
deletion-containing alleles in a single reaction, without
variants may not necessarily occur in genic regions, but in
necessarily sequencing the PCR products. When these
gene regulatory regions such as those described by the
data showed that the deletion was enriched in resistant
ENCODE project18).
populations, functional effects of the deletion polymor-
While the discovery was made in CML, the biology and
phism were then investigated at the mechanistic level at
clinical significance was extended to EGFR NSCLC. Here,
the bench.
we observed that the deletion mediated intrinsic resist-
Finally, two other important factors in the process of
ance to EGFR inhibitors in cell lines, and that the deletion
discovery should be mentioned. The first was the role
shortened the PFS from 11.9 to 6.6 months in patients
（1716）170
臨
床
血
液 54：10
without and with the deletion polymorphism respectively.
immune surveillance. Given the known effects of BIM
Two other groups have since published data regarding the
haploinsufficiency on immune cell function23∼25) and the
BIM deletion polymorphism in EGFR NSCLC. The first
documented anti-leukemia cell effect of T and NK cells26),
19)
was by Dr. Seiji YanoBs group from Kanazawa University .
this idea certainly offers a plausible explanation for their
These investigators discovered a novel EGFR NSCLC cell
data. In this respect, it would be interesting to determine if
line with the BIM deletion polymorphism, and demon-
rates of relapse among allografted CML patients might be
strated that it had the expected phenotype comprising
different depending on the BIM deletion status of the
intrinsic resistance to EGFR TKIs, increased splicing of
donor. Additionally, alternative explanations should also
BIM exon 3 at the expense of exon 4, and decreased ex-
be considered for the findings of Katagiri et al. Given that
pression of BH3-containing BIM isoforms. More impor-
patients with CML are closely monitored for benchmark
tantly, they made the intriguing finding that the histone
responses (usually by measuring the proportion of
deacetylase inhibitor, vorinostat, is able to restore the
Philadelphia chromosome positive cells in blood and/or
aberrant splicing of BIM to favor exon 4 over exon 3,
bone marrow, as well as by quantitative RT-PCR for BCR-
resulting in expression of BH3-containing BIM isoforms,
ABL1 transcripts), it could be possible that those
and resensitization to EGFR TKIs. As stated by the
individuals with suboptimal responses may have had their
authors, the exact mechanism by which vorinostat alters
TKI doses increased or their TKI changed to more potent
BIM splicing remains to be elucidated, although they
second generation drugs. Furthermore, it should be
noted that effects of vorinostat on mRNA splicing have
highlighted that the BIM deletion polymorphism confers
previously been described20). In addition to data support-
relative and not absolute TKI resistance, and as such, the
ing our initial discovery, we also take note of a recent
increases in drug dose and/or potency would be expected
publication by a group from Korea with contrary results21).
to result in increased responses. Because CML progeni-
This group performed a retrospective analysis of 197 pa-
tors are thought to act as reservoirs for relapse27), another
tients with EGFR NSCLC and concluded that several
possible explanation could be that the deletion polymor-
factors, including the BIM deletion polymorphism,
phism modulates leukemia stem cell survival and/or main-
treatment type, EGFR genotype, or smoking did not
tenance. This possibility is consistent with the inability of
predict inferior PFS. Ideally, studies to determine the role
clinical tests to reliably detect or quantify residual CML
of the BIM deletion polymorphism should be prospective
LSCs in patients28), and the recently described reliance of
and include large cohorts of patients, and indeed such a
CML LSCs on BCL2 family members for maintenance29).
study is under way at the National Cancer Centre in
Singapore.
More work to be done
With regard to CML, a small study by Katagiri et al.
In addition to CML and EGFR NSCLC, several other
from Tokyo Medical University has suggested that the
human cancers have been documented to be critically
BIM deletion polymorphism might be used as a criterion
dependent on BIM for drug sensitivity. These include c-
for discontinuation of imatinib in CML22). These authors
KIT-driven gastrointestinal tumors (imatinib resistance),
determined the incidence of the BIM deletion polymor-
JAK2-mutated myeloproliferative disorders (JAK2 inhibi-
phism among patients with CML treated with TKIs, and
tor resistance), and acute lymphoblastic leukemia (ALL)
who had achieved a complete molecular remission (CMR).
(steroid resistance)30∼32). It would therefore be important
Interestingly, out of 5 patients who were able to remain in
to determine if patients with the BIM deletion polymor-
CMR 12 months after stopping TKI therapy, all 5 were
phism do indeed experience inferior responses to the
negative for the deletion. In contrast, out of 8 patients who
above agents, and if so, could they be resensitized using
achieved CMR and had disease relapse within 12 months
drugs that restore BIM splicing patterns or replace BIM
of TKI cessation, 3 had the deletion polymorphism. While
function. In performing such studies, it should also be
the data is not conclusive (given the small number of pa-
noted that concurrent therapy, including cytotoxic agents,
tients), it is nevertheless very intriguing, and led the
may introduce confounding factors. For example, in ALL,
authors to suggest that the deletion polymorphism may be
two agents which are commonly used in induction therapy
influencing relapse rates via affecting the function of T
are vincristine and L-asparaginase, and both have been
and/or NK cells, which in turn are responsible for
described to kill cancer cells by modulating levels of BCL171（1717）
−臨
床
血
液−
2 family members33, 34). Thus, any negative clinical effects
References
of the BIM deletion polymorphism regarding steroid
responsiveness may be counteracted by the ability of
1）Jänne PA, Gray N, Settleman J. Factors underlying sensitivity
cytotoxics to tip the overall apoptotic threshold toward cell
of cancers to small-molecule kinase inhibitors. Nat Rev Drug
Discov. 2009; 8: 709-723.
death.
Because several agents have now been found to reverse
TKI resistance conferred by the BIM deletion polymor-
2）Carella AM, Frassoni F, Melo J, et al. New insights in biology
and current therapeutic options for patients with chronic
myelogenous leukemia. Haematologica. 1997; 82: 478-495.
phism, including BH3 mimetic drugs and HDAC inhibi-
3）Schiller JH, Harrington D, Belani CP, et al. Comparison of
tors4, 35), it is now important to test these combinations in
four chemotherapy regimens for advanced non-small-cell
patients. It remains to be seen whether or not such studies
lung cancer. N Engl J Med. 2002; 346: 92-98.
will include patients without the BIM deletion polymor-
4）Ng KP, Hillmer AM, Chuah CT, et al. A common BIM
phism, since in vitro work suggests that patients with and
deletion polymorphism mediates intrinsic resistance and
without the deletion may both benefit from BH3 mimetic/
inferior responses to tyrosine kinase inhibitors in cancer. Nat
TKI combinations.
Finally, two other questions have been raised by our
discovery. The first relates to the high frequency of the
Med. 2012; 18: 521-528.
5）Adams JM, Huang DC, Strasser A, et al. Subversion of the
Bcl-2 life/death switch in cancer development and therapy.
Cold Spring Harb Symp Quant Biol. 2005; 70: 469-477.
deletion polymorphism is in East Asians, and its non-
6）Cragg MS, Harris C, Strasser A, Scott CL. Unleashing the
existence in African or Caucasian individuals. Given the
power of inhibitors of oncogenic kinases through BH3
known role of BIM in immune cell function, could the
mimetics. Nat Rev Cancer. 2009; 9: 321-326.
deletion confer a survival advantage against environ-
7）Roche-Lestienne C, Soenen-Cornu V, Grardel-Duflos N, et al.
mental pathogens? Second, given the established role of
Several types of mutations of the Abl gene can be found in
BIM as a tumor suppressor, could it be cooperating with
acquired EGFR mutations to transform lung epithelium,
and thus explain the increased incidence of EGFR NSCLC
in East Asia compared to the West?
In summary, the discovery of the BIM deletion
chronic myeloid leukemia patients resistant to STI571, and
they can pre-exist to the onset of treatment. Blood. 2002;
100: 1014-1018.
8）Wheeler HE, Maitland ML, Dolan ME, Cox NJ, Ratain MJ.
Cancer pharmacogenomics: strategies and challenges. Nat
Rev Genet. 2012; 14: 23-34.
polymorphism has helped us to understand how germline
9）Mauro MJ. Defining and managing imatinib resistance.
variants affecting key genes regulating cell survival and
Hematology Am Soc Hematol Educ Program. 2006; 2006:
death can have profound effects in the cancer clinic. The
discovery has also explained in part why heterogeneous
responses to targeted cancer therapies occur, even in
cohorts of molecular-defined homogenous cancers. Finally, by elucidating how the BIM deletion impairs the
219-225.
10）Navin N, Kendall J, Troge J, et al. Tumour evolution inferred
by single-cell sequencing. Nature. 2011; 472: 90-94.
11）Kantarjian H, Giles F, Wunderle L, et al. Nilotinib in imatinibresistant CML and Philadelphia chromosome-positive ALL. N
Engl J Med. 2006; 354: 2542-2551.
apoptotic response to TKIs, we now have an opportunity to
12）Kuribara R, Honda H, Matsui H, et al. Roles of Bim in
overcome this resistance not only in CML but also other
apoptosis of normal and Bcr-Abl-expressing hematopoietic
progenitors. Mol Cell Biol. 2004; 24: 6172-6183.
cancers.
13）Kuroda J, Puthalakath H, Cragg MS, et al. Bim and Bad
Acknowledgements
We would like to acknowledge the many co-authors and
mediate imatinib-induced killing of Bcr/Abl+ leukemic cells,
and resistance due to their loss is overcome by a BH3
mimetic. Proc Natl Acad Sci U S A. 2006; 103: 14907-14912.
collaborators who contributed their time and effort to the
14）Kubonishi I, Miyoshi I. Establishment of a Ph1 chromosome-
discovery of the BIM deletion polymorphism4) , and the
positive cell line from chronic myelogenous leukemia in blast
cancer patients in Japan, Malaysia, and Singapore, as well
as their treating physicians, for providing samples for analysis.
crisis. Int J Cell Cloning. 1983; 1: 105-117.
15）Egle A, Harris AW, Bouillet P, Cory S. Bim is a suppressor of
Myc-induced mouse B cell leukemia. Proc Natl Acad Sci U S
A. 2004; 101: 6164-6169.
The authors declare that they have no conflict of interest.
（1718）172
16）Au WY, Caguioa PB, Chuah C, et al. Chronic myeloid leukemia in Asia. Int J Hematol. 2009; 89: 14-23.
臨
17）Pao W, Miller VA. Epidermal growth factor receptor
床
血
液 54：10
2006; 95: 249-292.
mutations, small-molecule kinase inhibitors, and non-small-
27）Helgason GV, Young GA, Holyoake TL. Targeting chronic
cell lung cancer: current knowledge and future directions. J
myeloid leukemia stem cells. Curr Hematol Malig Rep. 2010;
Clin Oncol. 2005; 23: 2556-2568.
5: 81-87.
18）The ENCODE Project Consortium, Birney E, Stamatoyanno-
28）Bhatia R, Holtz M, Niu N, et al. Persistence of malignant
poulos JA, et al. Identification and analysis of functional
hematopoietic progenitors in chronic myelogenous leukemia
elements in 1％ of the human genome by the ENCODE pilot
patients in complete cytogenetic remission following imatinib
project. Nature. 2007; 447: 799-816.
mesylate treatment. Blood. 2003; 101: 4701-4707.
19）Nakagawa T, Takeuchi S, Yamada T, et al. EGFR-TKI
29）Goff DJ, Recart AC, Sadarangani A, et al. A Pan-BCL2 inhibi-
Resistance Due to BIM Polymorphism Can Be Circumvented
tor renders bone-marrow-resident human leukemia stem
in Combination with HDAC Inhibition. Cancer Res. 2013; 73:
cells sensitive to tyrosine kinase inhibition. Cell Stem Cell.
2428-2434.
2013; 12: 316-328.
20）Delcuve GP, Khan DH, Davie JR. Roles of histone
30）Gordon PM, Fisher DE. Role for the proapoptotic factor BIM
deacetylases in epigenetic regulation: emerging paradigms
in mediating imatinib-induced apoptosis in a c-KIT-
from studies with inhibitors. Clin Epigenetics. 2012; 4: 5.
dependent gastrointestinal stromal tumor cell line. J Biol
21）Lee JK, Shin JY, Kim S, et al. Primary resistance to epidermal
Chem. 2010; 285: 14109-14114.
growth factor receptor (EGFR) tyrosine kinase inhibitors
31）Will B, Siddiqi T, Jordà MA, et al. Apoptosis induced by JAK2
(TKIs) in patients with non-small-cell lung cancer harboring
inhibition is mediated by Bim and enhanced by the BH3
TKI-sensitive EGFR mutations: an exploratory study. Ann
mimetic ABT-737 in JAK2 mutant human erythroid cells.
Oncol. Prepublished on Apr 4, 2013, as doi: 10.1093/annonc/
mdt127.
22）Katagiri S, Umezu T, Ohyashiki JH, Ohyashiki K. The
Blood. 2010; 115: 2901-2909.
32）Abrams MT, Robertson NM, Yoon K, Wickstrom E.
Inhibition of glucocorticoid-induced apoptosis by targeting
BCL2L11(BIM)deletion polymorphism is a possible criterion
the major splice variants of BIM mRNA with small interfering
for discontinuation of imatinib in chronic myeloid leukaemia
RNA and short hairpin RNA. J Biol Chem. 2004; 279: 55809-
patients. Br J Haematol. 2013; 160: 269-271.
55817.
23）Willis SN, Adams JM. Life in the balance: how BH3-only
33）Wertz IE, Kusam S, Lam C, et al. Sensitivity to antitubulin
proteins induce apoptosis. Curr Opin Cell Biol. 2005; 17: 617-
chemotherapeutics is regulated by MCL1 and FBW7. Nature.
625.
2011; 471: 110-114.
24）Bouillet P, Huang DC, OBReilly LA, et al. The role of the pro-
34）High LM, Szymanska B, Wilczynska-Kalak U, et al. The Bcl-2
apoptotic Bcl-2 family member bim in physiological cell
homology domain 3 mimetic ABT-737 targets the apoptotic
death. Ann N Y Acad Sci. 2000; 926: 83-89.
machinery in acute lymphoblastic leukemia resulting in
25）Huntington ND, Puthalakath H, Gunn P, et al. Interleukin 15mediated survival of natural killer cells is determined by
interactions among Bim, Noxa and Mcl-1. Nat Immunol.
2007; 8: 856-863.
26）Sentman CL, Barber MA, Barber A, Zhang T. NK cell receptors as tools in cancer immunotherapy. Adv Cancer Res.
synergistic in vitro and in vivo interactions with established
drugs. Mol Pharmacol. 2010; 77: 483-494.
35）Nakagawa T, Takeuchi S, Yamada T, et al. EGFR-TKI
Resistance Due to BIM Polymorphism Can Be Circumvented
in Combination with HDAC Inhibition. Cancer Res. 2013; 73:
2428-2434.
173（1719）