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CHRONIC MYELOGENOUS LEUKEMIA

The BIM deletion polymorphism potentiates the survival of leukemia stem and progenitor cells and impairs response to targeted therapies

Leukemia volume 39, pages 134–143 (2025)Cite this article

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Abstract

One sixth of human cancers harbor pathogenic germline variants, but few studies have established their functional contribution to cancer outcomes. Here, we developed a humanized mouse model harboring a common East Asian polymorphism, the BIM deletion polymorphism (BDP), which confers resistance to oncogenic kinase inhibitors through generation of non-apoptotic splice isoforms. However, despite its clear role in mediating bulk resistance in patients, the BDP’s role in cancer stem and progenitor cells, which initiate disease and possess altered BCL-2 rheostats compared to differentiated tumor cells, remains unknown. To study the role of the BDP in leukemia initiation, we crossed the BDP mouse into a chronic myeloid leukemia (CML) model. We found that the BDP greatly enhanced the fitness of CML cells with a three-fold greater competitive advantage, leading to more aggressive disease. The BDP conferred almost complete resistance to cell death induced by imatinib in CML stem and progenitor cells (LSPCs). Using BH3 profiling, we identified a novel therapeutic vulnerability of BDP LSPCs to MCL-1 antagonists, which we confirmed in primary human LSPCs, and in vivo. Our findings demonstrate the impact of human polymorphisms on the survival of LSPCs and highlight their potential as companion diagnostics for tailored therapies.

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Fig. 1: Characterization of the hBim mouse.
Fig. 2: The BDP induces more aggressive CML.
Fig. 3: The BDP induces more aggressive CML by enhancing LSPC survival.
Fig. 4: The BDP confers IM resistance in CML LSPCs.
Fig. 5: Identification of therapeutic vulnerabilities in i2–/–;BCR::ABL1 CML LSPCs by BH3 profiling.

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Data availability

All data generated or analyzed during this study are included in this published article and its supplementary information files.

References

  1. Ku CS, Loy EY, Salim A, Pawitan Y, Chia KS. The discovery of human genetic variations and their use as disease markers: past, present and future. J Hum Genet. 2010;55:403–15.

    PubMed  Google Scholar 

  2. Thavaneswaran S, Rath E, Tucker K, Joshua AM, Hess D, Pinese M, et al. Therapeutic implications of germline genetic findings in cancer. Nat Rev Clin Oncol. 2019;16:386–96.

    CAS  PubMed  Google Scholar 

  3. Wu D, Dou J, Chai X, Bellis C, Wilm A, Shih CC, et al. Large-scale whole-genome sequencing of three diverse asian populations in Singapore. Cell. 2019;179:736–49.e15.

    CAS  PubMed  Google Scholar 

  4. Marum JE, Yeung DT, Purins L, Reynolds J, Parker WT, Stangl D, et al. ASXL1 and BIM germ line variants predict response and identify CML patients with the greatest risk of imatinib failure. Blood Adv. 2017;1:1369–81.

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Menden MP, Casale FP, Stephan J, Bignell GR, Iorio F, McDermott U, et al. The germline genetic component of drug sensitivity in cancer cell lines. Nat Commun. 2018;9:3385.

    PubMed  PubMed Central  Google Scholar 

  6. Yang H, Zhang H, Luan Y, Liu T, Yang W, Roberts KG, et al. Noncoding genetic variation in GATA3 increases acute lymphoblastic leukemia risk through local and global changes in chromatin conformation. Nat Genet. 2022;54:170–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Chan SH, Bylstra Y, Teo JX, Kuan JL, Bertin N, Gonzalez-Porta M, et al. Analysis of clinically relevant variants from ancestrally diverse Asian genomes. Nat Commun. 2022;13:6694.

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Ng KP, Hillmer AM, Chuah CT, Juan WC, Ko TK, Teo AS, et al. A common BIM deletion polymorphism mediates intrinsic resistance and inferior responses to tyrosine kinase inhibitors in cancer. Nat Med. 2012;18:521–8.

    CAS  PubMed  Google Scholar 

  9. Soh SX, Siddiqui FJ, Allen JC, Kim GW, Lee JC, Yatabe Y, et al. A systematic review and meta-analysis of individual patient data on the impact of the BIM deletion polymorphism on treatment outcomes in epidermal growth factor receptor mutant lung cancer. Oncotarget. 2017;8:41474–86.

    PubMed  PubMed Central  Google Scholar 

  10. Cardona AF, Rojas L, Wills B, Arrieta O, Carranza H, Vargas C, et al. BIM deletion polymorphisms in Hispanic patients with non-small cell lung cancer carriers of EGFR mutations. Oncotarget. 2016;7:68933–42.

    PubMed  PubMed Central  Google Scholar 

  11. Costa DB, Halmos B, Kumar A, Schumer ST, Huberman MS, Boggon TJ, et al. BIM mediates EGFR tyrosine kinase inhibitor-induced apoptosis in lung cancers with oncogenic EGFR mutations. PLoS Med. 2007;4:1669–79.

    CAS  PubMed  Google Scholar 

  12. Cragg MS, Jansen ES, Cook M, Harris C, Strasser A, Scott CL. Treatment of B-RAF mutant human tumor cells with a MEK inhibitor requires Bim and is enhanced by a BH3 mimetic. J Clin Invest. 2008;118:3651–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Liu J, Bhadra M, Sinnakannu JR, Yue WL, Tan CW, Rigo F, et al. Overcoming imatinib resistance conferred by the BIM deletion polymorphism in chronic myeloid leukemia with splice-switching antisense oligonucleotides. Oncotarget. 2017;8:77567–85.

    PubMed  PubMed Central  Google Scholar 

  14. Ciechomska IA, Gielniewski B, Wojtas B, Kaminska B, Mieczkowski J. EGFR/FOXO3a/BIM signaling pathway determines chemosensitivity of BMP4-differentiated glioma stem cells to temozolomide. Exp Mol Med. 2020;52:1326–40.

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Song T, Guo Y, Xue Z, Guo Z, Wang Z, Lin D, et al. Small-molecule inhibitor targeting the Hsp70-Bim protein-protein interaction in CML cells overcomes BCR-ABL-independent TKI resistance. Leukemia. 2021;35:2862–74.

    CAS  PubMed  Google Scholar 

  16. Katagiri S, Umezu T, Ohyashiki JH, Ohyashiki K. The BCL2L11 (BIM) deletion polymorphism is a possible criterion for discontinuation of imatinib in chronic myeloid leukaemia patients. Br J Haematol. 2013;160:269–71.

    CAS  PubMed  Google Scholar 

  17. Than H, Lye WK, Sng C, Allen JC Jr., Ong ST, Chuah C. BIM deletion polymorphism profiling complements prognostic values of risk scores in imatinib-treated Asian chronic myeloid leukemia patients. Leuk Lymphoma. 2019;60:234–7.

    CAS  PubMed  Google Scholar 

  18. Vetrie D, Helgason GV, Copland M. The leukaemia stem cell: similarities, differences and clinical prospects in CML and AML. Nat Rev Cancer. 2020;20:158–73.

    CAS  PubMed  Google Scholar 

  19. Su H, Trombly MI, Chen J, Wang X. Essential and overlapping functions for mammalian Argonautes in microRNA silencing. Genes Dev. 2009;23:304–17.

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Pernaute B, Spruce T, Smith KM, Sanchez-Nieto JM, Manzanares M, Cobb B, et al. MicroRNAs control the apoptotic threshold in primed pluripotent stem cells through regulation of BIM. Genes Dev. 2014;28:1873–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Bouillet P, Metcalf D, Huang DC, Tarlinton DM, Kay TW, Kontgen F, et al. Proapoptotic Bcl-2 relative Bim required for certain apoptotic responses, leukocyte homeostasis, and to preclude autoimmunity. Science. 1999;286:1735–8.

    CAS  PubMed  Google Scholar 

  22. Kuribara R, Honda H, Matsui H, Shinjyo T, Inukai T, Sugita K, et al. Roles of Bim in apoptosis of normal and Bcr-Abl-expressing hematopoietic progenitors. Mol Cell Biol. 2004;24:6172–83.

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Kozuma Y, Ninomiya H, Murata S, Kono T, Mukai HY, Kojima H. The pro-apoptotic BH3-only protein Bim regulates cell cycle progression of hematopoietic progenitors during megakaryopoiesis. J Thromb Haemost. 2010;8:1088–97.

    CAS  PubMed  Google Scholar 

  24. Labi V, Bertele D, Woess C, Tischner D, Bock FJ, Schwemmers S, et al. Haematopoietic stem cell survival and transplantation efficacy is limited by the BH3-only proteins Bim and Bmf. EMBO Mol Med. 2013;5:122–36.

    CAS  PubMed  Google Scholar 

  25. Leidy-Davis T, Cheng K, Goodwin LO, Morgan JL, Juan WC, Roca X, et al. Viable mice with extensive gene humanization (25-kbp) created using embryonic stem cell/blastocyst and CRISPR/Zygote injection approaches. Sci Rep. 2018;8:15028.

    PubMed  PubMed Central  Google Scholar 

  26. Koschmieder S, Gottgens B, Zhang P, Iwasaki-Arai J, Akashi K, Kutok JL, et al. Inducible chronic phase of myeloid leukemia with expansion of hematopoietic stem cells in a transgenic model of BCR-ABL leukemogenesis. Blood. 2005;105:324–34.

    CAS  PubMed  Google Scholar 

  27. Zhang B, Ho YW, Huang Q, Maeda T, Lin A, Lee SU, et al. Altered microenvironmental regulation of leukemic and normal stem cells in chronic myelogenous leukemia. Cancer Cell. 2012;21:577–92.

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Butow M, Testaquadra FJ, Baumeister J, Maie T, Chatain N, Jaquet T, et al. Targeting cytokine-induced leukemic stem cell persistence in chronic myeloid leukemia by IKK2-inhibition. Haematologica. 2023;108:1179–85.

    PubMed  Google Scholar 

  29. Kotschy A, Szlavik Z, Murray J, Davidson J, Maragno AL, Le Toumelin-Braizat G, et al. The MCL1 inhibitor S63845 is tolerable and effective in diverse cancer models. Nature. 2016;538:477–82.

    PubMed  Google Scholar 

  30. Kotecha N, Krutzik PO, Irish JM. Web-based analysis and publication of flow cytometry experiments. Curr Protoc Cytom. 2010;Chapter 10:Unit10 7.

    Google Scholar 

  31. Olesinski EA, Bhatt S. Dynamic BH3 profiling method for rapid identification of active therapy in BH3 mimetics resistant xenograft mouse models. STAR Protoc. 2021;2:100461.

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Carter BZ, Mak PY, Mu H, Zhou H, Mak DH, Schober W, et al. Combined targeting of BCL-2 and BCR-ABL tyrosine kinase eradicates chronic myeloid leukemia stem cells. Sci Transl Med. 2016;8:355ra117.

    PubMed  PubMed Central  Google Scholar 

  33. Del Gaizo Moore V, Letai A. BH3 profiling-measuring integrated function of the mitochondrial apoptotic pathway to predict cell fate decisions. Cancer Lett. 2013;332:202–5.

    PubMed  Google Scholar 

  34. Fraser C, Ryan J, Sarosiek K. BH3 profiling: a functional assay to measure apoptotic priming and dependencies. Methods Mol Biol. 2019;1877:61–76.

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Amabile G, Di Ruscio A, Muller F, Welner RS, Yang H, Ebralidze AK, et al. Dissecting the role of aberrant DNA methylation in human leukaemia. Nat Commun. 2015;6:7091.

    PubMed  Google Scholar 

  36. Villani A, Davidson S, Kanwar N, Lo WW, Li Y, Cohen-Gogo S, et al. The clinical utility of integrative genomics in childhood cancer extends beyond targetable mutations. Nat Cancer. 2023;4:203–21.

    CAS  PubMed  Google Scholar 

  37. Egle A, Harris AW, Bouillet P, Cory S. Bim is a suppressor of Myc-induced mouse B cell leukemia. Proc Natl Acad Sci USA. 2004;101:6164–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Grabow S, Kueh AJ, Ke F, Vanyai HK, Sheikh BN, Dengler MA, et al. Subtle Changes in the Levels of BCL-2 Proteins Cause Severe Craniofacial Abnormalities. Cell Rep. 2018;24:3285–95.e4.

    CAS  PubMed  Google Scholar 

  39. Pei S, Pollyea DA, Gustafson A, Stevens BM, Minhajuddin M, Fu R, et al. Monocytic subclones confer resistance to venetoclax-based therapy in patients with acute myeloid leukemia. Cancer Discov. 2020;10:536–51.

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Merino D, Kelly GL, Lessene G, Wei AH, Roberts AW, Strasser A. BH3-mimetic drugs: blazing the trail for new cancer medicines. Cancer Cell. 2018;34:879–91.

    CAS  PubMed  Google Scholar 

  41. Lagadinou ED, Sach A, Callahan K, Rossi RM, Neering SJ, Minhajuddin M, et al. BCL-2 inhibition targets oxidative phosphorylation and selectively eradicates quiescent human leukemia stem cells. Cell Stem Cell. 2013;12:329–41.

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Delbridge AR, Opferman JT, Grabow S, Strasser A. Antagonism between MCL-1 and PUMA governs stem/progenitor cell survival during hematopoietic recovery from stress. Blood. 2015;125:3273–80.

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Krishnan V, Schmidt F, Nawaz Z, Venkatesh PN, Lee KL, Ren X, et al. A single-cell atlas identifies pretreatment features of primary imatinib resistance in chronic myeloid leukemia. Blood. 2023;141:2738–55.

    CAS  PubMed  Google Scholar 

  44. Ilander M, Olsson-Stromberg U, Schlums H, Guilhot J, Bruck O, Lahteenmaki H, et al. Increased proportion of mature NK cells is associated with successful imatinib discontinuation in chronic myeloid leukemia. Leukemia. 2017;31:1108–16.

    CAS  PubMed  Google Scholar 

  45. Irani YD, Hughes A, Clarson J, Kok CH, Shanmuganathan N, White DL, et al. Successful treatment-free remission in chronic myeloid leukaemia and its association with reduced immune suppressors and increased natural killer cells. Br J Haematol. 2020;191:433–41.

    CAS  PubMed  Google Scholar 

  46. Hsieh YC, Kirschner K, Copland M. Improving outcomes in chronic myeloid leukemia through harnessing the immunological landscape. Leukemia. 2021;35:1229–42.

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Min-Oo G, Bezman NA, Madera S, Sun JC, Lanier LL. Proapoptotic Bim regulates antigen-specific NK cell contraction and the generation of the memory NK cell pool after cytomegalovirus infection. J Exp Med. 2014;211:1289–96.

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Ishiyama K, Kitawaki T, Sugimoto N, Sozu T, Anzai N, Okada M, et al. Principal component analysis uncovers cytomegalovirus-associated NK cell activation in Ph(+) leukemia patients treated with dasatinib. Leukemia. 2017;31:268.

    CAS  PubMed  Google Scholar 

  49. Green ML, Leisenring WM, Xie H, Walter RB, Mielcarek M, Sandmaier BM, et al. CMV reactivation after allogeneic HCT and relapse risk: evidence for early protection in acute myeloid leukemia. Blood. 2013;122:1316–24.

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Chougnet CA, Tripathi P, Lages CS, Raynor J, Sholl A, Fink P, et al. A major role for Bim in regulatory T cell homeostasis. J Immunol 2011;186:156–63.

    CAS  PubMed  Google Scholar 

  51. Nishihara S, Yamaoka T, Ishikawa F, Higuchi K, Hasebe Y, Manabe R, et al. Mechanisms of EGFR-TKI-induced apoptosis and strategies targeting apoptosis in EGFR-mutated non-small cell lung cancer. Genes (Basel). 2022;13:2183.

  52. Lee JH, Lin YL, Hsu WH, Chen HY, Chang YC, Yu CJ, et al. Bcl-2-like protein 11 deletion polymorphism predicts survival in advanced non-small-cell lung cancer. J Thorac Oncol. 2014;9:1385–92.

    CAS  PubMed  Google Scholar 

  53. Zhao M, Zhang Y, Cai W, Li J, Zhou F, Cheng N, et al. The Bim deletion polymorphism clinical profile and its relation with tyrosine kinase inhibitor resistance in Chinese patients with non-small cell lung cancer. Cancer. 2014;120:2299–307.

    CAS  PubMed  Google Scholar 

  54. Atsumi J, Shimizu K, Ohtaki Y, Kaira K, Kakegawa S, Nagashima T, et al. Impact of the bim deletion polymorphism on survival among patients with completely resected non-small-cell lung carcinoma. J Glob Oncol. 2016;2:15–25.

    PubMed  Google Scholar 

  55. Su W, Zhang X, Cai X, Peng M, Wang F, Wang Y. BIM deletion polymorphism predicts poor response to EGFR-TKIs in nonsmall cell lung cancer: An updated meta-analysis. Med (Balt). 2019;98:e14568.

    CAS  Google Scholar 

  56. Xia J, Bai H, Yan B, Li R, Shao M, Xiong L, et al. Mimicking the BIM BH3 domain overcomes resistance to EGFR tyrosine kinase inhibitors in EGFR-mutant non-small cell lung cancer. Oncotarget. 2017;8:108522–33.

    PubMed  PubMed Central  Google Scholar 

  57. Kleczko EK, Le AT, Hinz TK, Nguyen TT, Navarro A, Hu CJ, et al. Novel EGFR-mutant mouse models of lung adenocarcinoma reveal adaptive immunity requirement for durable osimertinib response. Cancer Lett. 2023;556:216062.

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Schrader KA, Cheng DT, Joseph V, Prasad M, Walsh M, Zehir A, et al. Germline Variants in Targeted Tumor Sequencing Using Matched Normal DNA. JAMA Oncol. 2016;2:104–11.

    PubMed  PubMed Central  Google Scholar 

  59. Mandelker D, Zhang L, Kemel Y, Stadler ZK, Joseph V, Zehir A, et al. Mutation detection in patients with advanced cancer by universal sequencing of cancer-related genes in tumor and normal DNA vs guideline-based germline testing. JAMA. 2017;318:825–35.

    PubMed  PubMed Central  Google Scholar 

  60. Grobner SN, Worst BC, Weischenfeldt J, Buchhalter I, Kleinheinz K, Rudneva VA, et al. The landscape of genomic alterations across childhood cancers. Nature. 2018;555:321–7.

    PubMed  Google Scholar 

  61. Deininger MW, Shah NP, Altman JK, Berman E, Bhatia R, Bhatnagar B, et al. Chronic myeloid leukemia, version 2.2021, NCCN clinical practice guidelines in oncology. J Natl Compr Canc Netw. 2020;18:1385–415.

    CAS  PubMed  Google Scholar 

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Acknowledgements

We thank Dr. Daniel Tenen for providing the ScltTA;BCR::ABL1 mice, Dr. Phillip Koeffler for providing the CD45.1 Pepboys. and Dr. Andreas Strasser for providing the anti-BimEL/L/S antibody (WEHI, Clone 3C5). We also wish to thank Tiffany Leidy-Davis for her efforts in creating the hBim mouse. We thank Messrs. Dianyan Guo and Ahmad Bin Mohamed Lajam for contributing to CyTOF analysis.

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  1. These authors contributed equally: Mengge Yu, Giselle Sek Suan Nah.

Authors and Affiliations

  1. Cancer and Stem Cell Biology, Duke-NUS Medical School, Singapore, 169857, Singapore

    Mengge Yu, Giselle Sek Suan Nah, Vaidehi Krishnan, Fatin Nasha Bte Sulaimi, King Pan Ng, Charles Chuah & S. Tiong Ong

  2. KK Women’s and Children’s Hospital, Singapore, 229899, Singapore

    King Pan Ng

  3. Department of Pharmacy, National University of Singapore, Singapore, 117559, Singapore

    Chuqi Wang & Shruti Bhatt

  4. Department of Haematology, Singapore General Hospital, Singapore, 169608, Singapore

    Charles Chuah & S. Tiong Ong

  5. The Jackson Laboratory, Bar Harbor, ME, 04609, USA

    David E. Bergstrom

  6. Division of Hematologic Malignancies and Cellular Therapy, Duke University Medical Center, Durham, NC, 27708, USA

    S. Tiong Ong

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Contributions

MY, GSSN, and STO designed research; MY, GSSN, VK, FNBS, KPN and WC performed research; CC and DEB contributed key human samples and the humanized Bim mouse model, respectively, and provided feedback on the report. MY, GSSN, and STO analyzed data and wrote the paper.

Corresponding author

Correspondence to S. Tiong Ong.

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The authors declare no competing interests.

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All methods were performed in accordance with the relevant guidelines and regulations of Duke-NUS. This includes obtaining informed consent from all participants who provided primary cells under approved NUS IRB study #LN-20-058E.

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Yu, M., Nah, G.S.S., Krishnan, V. et al. The BIM deletion polymorphism potentiates the survival of leukemia stem and progenitor cells and impairs response to targeted therapies. Leukemia 39, 134–143 (2025). https://doi.org/10.1038/s41375-024-02418-0

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