Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
Program in Developmental Biology, Baylor College of Medicine, Houston, TX 77030, USA.
Sci Adv. 2021 Jul 21;7(30). doi: 10.1126/sciadv.abf3895. Print 2021 Jul.
Metabolic dysregulation underlies malignant phenotypes attributed to cancer stem cells, such as unlimited proliferation and differentiation blockade. Here, we demonstrate that NAD metabolism enables acute myeloid leukemia (AML) to evade apoptosis, another hallmark of cancer stem cells. We integrated whole-genome CRISPR screening and pan-cancer genetic dependency mapping to identify and as AML dependencies governing NAD biosynthesis. While both and were required for AML, the presence of NAD precursors bypassed the dependence of AML on but not , pointing to as a gatekeeper of NAD biosynthesis. Deletion of reduced nuclear NAD, activated p53, and increased venetoclax sensitivity. Conversely, increased NAD biosynthesis promoted venetoclax resistance. Unlike leukemia stem cells (LSCs) in both murine and human AML xenograft models, was dispensable for hematopoietic stem cells and hematopoiesis. Our findings identify NMNAT1 as a previously unidentified therapeutic target that maintains NAD for AML progression and chemoresistance.
代谢失调是癌症干细胞恶性表型的基础，例如无限增殖和分化阻滞。在这里，我们证明 NAD 代谢使急性髓系白血病 (AML) 能够逃避细胞凋亡，这是癌症干细胞的另一个标志。我们整合了全基因组 CRISPR 筛选和泛癌遗传依赖性作图，以鉴定 和 作为调节 NAD 生物合成的 AML 依赖性。虽然 和 都需要 AML，但 NAD 前体的存在可以绕过 AML 对 的依赖，但不能绕过对 的依赖，这表明 是 NAD 生物合成的守门员。 删除 减少了核 NAD，激活了 p53，并增加了 venetoclax 的敏感性。相反，增加 NAD 生物合成会促进 venetoclax 耐药性。与在小鼠和人类 AML 异种移植模型中的白血病干细胞 (LSCs) 不同， 在造血干细胞和造血中是可有可无的。我们的研究结果确定了 NMNAT1 作为一个以前未被识别的治疗靶点，它维持了 NAD 的 AML 进展和化疗耐药性。
