2. Academic Validation
  3. The BIM deletion polymorphism potentiates the survival of leukemia stem and progenitor cells and impairs response to targeted therapies

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

  • Leukemia. 2024 Oct 22. doi: 10.1038/s41375-024-02418-0.
Mengge Yu # 1,  Giselle Sek Suan Nah # 1,  Vaidehi Krishnan 1,  Fatin Nasha Bte Sulaimi 1,  King Pan Ng 1 2,  Chuqi Wang 3,  Shruti Bhatt 3,  Charles Chuah 1 4,  David E Bergstrom 5,  S Tiong Ong 6 7 8
Affiliations

Affiliations

  • 1 Cancer and Stem Cell Biology, Duke-NUS Medical School, Singapore, 169857, Singapore.
  • 2 KK Women's and Children's Hospital, Singapore, 229899, Singapore.
  • 3 Department of Pharmacy, National University of Singapore, Singapore, 117559, Singapore.
  • 4 Department of Haematology, Singapore General Hospital, Singapore, 169608, Singapore.
  • 5 The Jackson Laboratory, Bar Harbor, ME, 04609, USA.
  • 6 Cancer and Stem Cell Biology, Duke-NUS Medical School, Singapore, 169857, Singapore. sintiong.ong@duke-nus.edu.sg.
  • 7 Department of Haematology, Singapore General Hospital, Singapore, 169608, Singapore. sintiong.ong@duke-nus.edu.sg.
  • 8 Division of Hematologic Malignancies and Cellular Therapy, Duke University Medical Center, Durham, NC, 27708, USA. sintiong.ong@duke-nus.edu.sg.
  • # Contributed equally.
PMID: 39438588 DOI: 10.1038/s41375-024-02418-0
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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