Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA.
Department of Stem Cell and Regenerative Biology and.
Blood. 2020 Sep 10;136(11):1303-1316. doi: 10.1182/blood.2019001808.
Metabolic alterations in cancer represent convergent effects of oncogenic mutations. We hypothesized that a metabolism-restricted genetic screen, comparing normal primary mouse hematopoietic cells and their malignant counterparts in an ex vivo system mimicking the bone marrow microenvironment, would define distinctive vulnerabilities in acute myeloid leukemia (AML). Leukemic cells, but not their normal myeloid counterparts, depended on the aldehyde dehydrogenase 3a2 (Aldh3a2) enzyme that oxidizes long-chain aliphatic aldehydes to prevent cellular oxidative damage. Aldehydes are by-products of increased oxidative phosphorylation and nucleotide synthesis in cancer and are generated from lipid peroxides underlying the non-caspase-dependent form of cell death, ferroptosis. Leukemic cell dependence on Aldh3a2 was seen across multiple mouse and human myeloid leukemias. Aldh3a2 inhibition was synthetically lethal with glutathione peroxidase-4 (GPX4) inhibition; GPX4 inhibition is a known trigger of ferroptosis that by itself minimally affects AML cells. Inhibiting Aldh3a2 provides a therapeutic opportunity and a unique synthetic lethality to exploit the distinctive metabolic state of malignant cells.
癌症中的代谢改变代表了致癌突变的趋同效应。我们假设，在体外系统中比较正常的原发性造血细胞与其恶性对应物，对代谢进行限制的遗传筛选，将在急性髓细胞白血病（AML）中定义独特的脆弱性。白血病细胞，但不是其正常髓样细胞，依赖于醛脱氢酶 3a2（Aldh3a2）酶，该酶将长链脂肪醛氧化为防止细胞氧化损伤。醛是癌症中氧化磷酸化和核苷酸合成增加的副产物，并且由脂质过氧化物产生，脂质过氧化物是细胞死亡的非胱天蛋白酶依赖性形式，即铁死亡的基础。在多种小鼠和人类髓性白血病中都观察到白血病细胞对 Aldh3a2 的依赖性。Aldh3a2 抑制与谷胱甘肽过氧化物酶 4（GPX4）抑制具有合成致死性；GPX4 抑制是铁死亡的已知触发因素，其本身对 AML 细胞的影响极小。抑制 Aldh3a2 为利用恶性细胞独特的代谢状态提供了治疗机会和独特的合成致死性。
