The BIM deletion polymorphism: A paradigm of a permissive interaction between germline and acquired TKI resistance factors in chronic myeloid leukemia

// Tun Kiat Ko 1 , Hui San Chin 2, 3 , Charles T.H. Chuah 1, 4 , John W.J. Huang 1, 8 , King-Pan Ng 1, 9 , Seong Lin Khaw 2, 3, 5 , David C.S. Huang 2, 3, 5 , S. Tiong Ong 1, 4, 6, 7 1 Cancer and Stem Cell Biology Program, Duke-NUS Graduate Medical School, Singapore 2 The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia 3 Department of Medical Biology, University of Melbourne, Parkville, VIC, Australia 4 Department of Haematology, Singapore General Hospital, Singapore 5 Royal Children's Hospital, Parkville, VIC, Australia 6 Department of Medical Oncology, National Cancer Centre, Singapore 7 Department of Medicine, Duke University Medical Center, Durham, NC, USA 8 Present address: Singapore Institute for Clinical Sciences (SICS), Brenner Centre for Molecular Medicine, Singapore 9 Present address: Cancer Science Institute of Singapore, National University of Singapore, Singapore Correspondence to: S. Tiong Ong, e-mail: sintiong.ong@duke-nus.edu.sg Keywords: BIM deletion polymorphism, CML, TKI resistance, BH3 mimetic, BCR-ABL1 Received: August 18, 2015      Accepted: October 16, 2015      Published: October 28, 2015 ABSTRACT Both germline polymorphisms and tumor-specific genetic alterations can determine the response of a cancer to a given therapy. We previously reported a germline deletion polymorphism in the BIM gene that was sufficient to mediate intrinsic resistance to tyrosine kinase inhibitors (TKI) in chronic myeloid leukemia (CML), as well as other cancers [ 1 ]. The deletion polymorphism favored the generation of BIM splice forms lacking the pro-apoptotic BH3 domain, conferring a relative resistance to the TKI imatinib (IM). However, CML patients with the BIM deletion polymorphism developed both partial and complete IM resistance. To understand the mechanisms underlying the latter, we grew CML cells either with or without the BIM deletion polymorphism in increasing IM concentrations. Under these conditions, the BIM deletion polymorphism enhanced the emergence of populations with complete IM resistance, mimicking the situation in patients. Importantly, the combined use of TKIs with the BH3 mimetic ABT-737 overcame the BCR-ABL1 -dependent and -independent resistance mechanisms found in these cells. Our results illustrate the interplay between germline and acquired genetic factors in confering TKI resistance, and suggest a therapeutic strategy for patients with complete TKI resistance associated with the BIM deletion polymorphism.