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

Tun Kiat Ko,Seong Lin Khaw,King-Pan Ng,S Tiong Ong,John W J Huang,David C S Huang,Charles T H Chuah,Hui San Chin

doi:10.18632/oncotarget.5436

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.

Highlights

The BCR-ABL1 gene fusion, a product of a chromosomal translocation involving chromosomes 9 and 22 [2, 3], encodes for a constitutively active tyrosine kinase that drives the pathogenesis of chronic myeloid leukemia (CML) [4,5,6,7,8,9]
We reported that CML patients with the BIM (Table 1) deletion polymorphism were at increased risk of experiencing inferior imatinib responses compared to those without [1]
By the end of 4 months, we found that cells harboring the BIM deletion polymorphism were more viable at ranges of imatinib (3 to 5 uM) corresponding to the maximal plasma imatinib concentrations tolerated by patients [20, 21]

Summary

Introduction

The BCR-ABL1 gene fusion, a product of a chromosomal translocation involving chromosomes 9 and 22 [2, 3], encodes for a constitutively active tyrosine kinase that drives the pathogenesis of chronic myeloid leukemia (CML) [4,5,6,7,8,9]. Germline polymorphisms and tumor-specific genetic mutations independently contribute to the behavior of human cancers, including the response to therapy. We recently reported a germline deletion polymorphism in the BIM gene that was sufficient to mediate intrinsic resistance to targeted therapies in cancer, including the examples of imatinib (IM) in CML and EGFR inhibitors in EGFR-mutated non-small www.impactjournals.com/oncotarget cell lung cancer (EGFR-NSCLC) [1]. CML cells maintain a survival advantage by suppressing BIM transcription and by targeting BIM for proteasomal degradation through MAPK1-dependent phosphorylation [11,12,13]. BIM up-regulation is required for TKIs to induce apoptosis, and suppression of BIM expression is sufficient to confer in vitro TKI resistance [11,12,13]

Methods

Results

Conclusion