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.

六分之一的人类癌症携带致病性种系变异，但很少有研究确定它们对癌症结果的功能贡献。在这里，我们开发了一种人源化小鼠模型，该模型具有常见的东亚多态性，即 BIM 缺失多态性 （BDP），它通过产生非凋亡剪接亚型赋予对致癌激酶抑制剂的抗性。然而，尽管 BDP 在介导患者的大量耐药性方面具有明确的作用，但 BDP 在癌症干细胞和祖细胞中的作用仍然未知，与分化的肿瘤细胞相比，BDP 在癌症干细胞和祖细胞中的作用是发病的，并具有改变的 BCL-2 变阻器。为了研究 BDP 在白血病发生中的作用，我们将 BDP 小鼠杂交到慢性粒细胞白血病 （CML） 模型中。我们发现 BDP 大大增强了 CML 细胞的适应性，竞争优势增加了三倍，导致更具侵袭性的疾病。BDP 对 CML 干细胞和祖细胞 （LSPC） 中伊马替尼诱导的细胞死亡几乎完全耐药。使用 BH3 分析，我们确定了 BDP LSPC 对 MCL-1 拮抗剂的新型治疗敏感性，我们在原代人 LSPC 和体内证实了这一点。我们的研究结果证明了人类多态性对 LSPC 存活的影响，并强调了它们作为定制疗法的伴随诊断的潜力。