Deregulation of the BCL2 gene family plays an important role in the pathogenesis of acute myeloid leukemia (AML). A BCL2 inhibitor, venetoclax, has received approval from the US Food and Drug Administration for the treatment of AML. However, upfront and acquired drug resistance ensues, in part due to the clinical and genetic heterogeneity of AML, highlighting the importance of identifying biomarkers to stratify patients onto the most effective therapies. By integrating clinical characteristics, exome and RNA sequencing, and inhibitor data from primary AML samples from patients, we determined that myelomonocytic leukemia and upregulation of BCL2A1 and CLEC7A, as well as mutations of PTPN11 and KRAS, conferred resistance to venetoclax and multiple venetoclax combinations. Venetoclax in combination with an MCL1 inhibitor, AZD5991, induced synthetic lethality and circumvented venetoclax resistance.

BCL2基因家族的失调在急性髓系白血病 (AML) 的发病机制中发挥着重要作用。 BCL2抑制剂venetoclax已获得美国食品和药物管理局批准用于治疗AML。然而，前期和获得性耐药性随之而来，部分原因是 AML 的临床和遗传异质性，这凸显了识别生物标志物对患者进行分层以采用最有效疗法的重要性。通过整合患者原发性 AML 样本的临床特征、外显子组和 RNA 测序以及抑制剂数据，我们确定粒单核细胞白血病、 BCL2A1和CLEC7A的上调以及PTPN11和KRAS的突变赋予了对 Venetoclax 和多种 Venetoclax 组合的耐药性。 Venetoclax 与 MCL1 抑制剂 AZD5991 联合使用，可诱导合成致死性并规避 Venetoclax 耐药性。