Acute myeloid leukemia (AML) results from the enhanced proliferation and impaired differentiation of hematopoietic stem and progenitor cells. Using an ex vivo functional screening assay, we identified that the combination of the BTK inhibitor ibrutinib and BCL2 inhibitor venetoclax (IBR + VEN), currently in clinical trials for chronic lymphocytic leukemia (CLL), demonstrated enhanced efficacy on primary AML patient specimens, AML cell lines, and in a mouse xenograft model of AML. Expanded analyses among a large cohort of hematologic malignancies (n = 651 patients) revealed that IBR + VEN sensitivity associated with selected genetic and phenotypic features in both CLL and AML specimens. Among AML samples, 11q23 MLL rearrangements were highly sensitive to IBR + VEN. Analysis of differentially expressed genes with respect to IBR + VEN sensitivity indicated pathways preferentially enriched in patient samples with reduced ex vivo sensitivity, including IL-10 signaling. These findings suggest that IBR + VEN may represent an effective therapeutic option for patients with AML.

中文翻译：

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ibrutinib 同时抑制激酶和 venetoclax 抑制 BCL2 为急性髓细胞白血病提供了一种治疗策略。

急性髓性白血病 (AML) 是造血干细胞和祖细胞增殖增强和分化受损的结果。使用离体功能筛选试验，我们发现目前处于慢性淋巴细胞白血病 (CLL) 临床试验中的 BTK 抑制剂 ibrutinib 和 BCL2 抑制剂 venetoclax (IBR + VEN) 的组合对原发性 AML 患者标本 AML 具有增强的疗效细胞系，以及在 AML 的小鼠异种移植模型中。对大量血液系统恶性肿瘤（n = 651 名患者）进行的扩展分析显示，IBR + VEN 敏感性与 CLL 和 AML 标本中选定的遗传和表型特征相关。在 AML 样本中，11q23 MLL 重排对 IBR + VEN 高度敏感。对 IBR + VEN 敏感性差异表达基因的分析表明，患者样本中优先富集的途径具有降低的离体敏感性，包括 IL-10 信号传导。这些发现表明 IBR + VEN 可能代表 AML 患者的有效治疗选择。