Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH, USA.
Department of Biomedical Engineering, The Ohio State University, Room 455C, OSUCCC Building, 410 West 12th Avenue, Columbus, OH, 43210, USA.
J Hematol Oncol. 2020 Oct 19;13(1):139. doi: 10.1186/s13045-020-00973-4.
Acute myeloid leukemia (AML) is a heterogeneous and complex disease, and treatments for this disease have not been curative for the majority of patients. In younger patients, internal tandem duplication of FLT3 (FLT3-ITD) is a common mutation for which two inhibitors (midostaurin and gilteritinib) with varied potency and specificity for FLT3 are clinically approved. However, the high rate of relapse or failed initial response of AML patients suggests that the addition of a second targeted therapy may be necessary to improve efficacy. Using an unbiased large-scale CRISPR screen, we genetically identified BCL2 knockout as having synergistic effects with an approved FLT3 inhibitor. Here, we provide supportive studies that validate the therapeutic potential of the combination of FLT3 inhibitors with venetoclax in vitro and in vivo against multiple models of FLT3-ITD-driven AML. Our unbiased approach provides genetic validation for co-targeting FLT3 and BCL2 and repurposes CRISPR screening data, utilizing the genome-wide scope toward mechanistic understanding.
急性髓系白血病（AML）是一种异质性和复杂的疾病，大多数患者的治疗方法尚未达到根治。在年轻患者中，FLT3 内部串联重复（FLT3-ITD）是一种常见的突变，针对这种突变，已有两种具有不同 FLT3 抑制效力和特异性的抑制剂（米哚妥林和吉特替尼）获得临床批准。然而，AML 患者复发率高或初始反应失败表明，可能需要添加第二种靶向治疗来提高疗效。通过使用无偏倚的大规模 CRISPR 筛选，我们从遗传上确定了 BCL2 敲除与已批准的 FLT3 抑制剂具有协同作用。在这里，我们提供了支持性研究，验证了 FLT3 抑制剂联合 venetoclax 在体外和体内针对多种 FLT3-ITD 驱动的 AML 模型的治疗潜力。我们的无偏方法为共同靶向 FLT3 和 BCL2 提供了遗传验证，并重新利用了 CRISPR 筛选数据，利用全基因组范围来深入了解机制。
