We characterize the metabolic background in distinct Acute Myeloid Leukemias (AMLs), by comparing the metabolism of primary AML blasts isolated at diagnosis with that of normal hematopoietic maturing progenitors, using the Seahorse XF Agilent. Leukemic cells feature lower spare respiratory (SRC) and glycolytic capacities as compared to hematopoietic precursors (i.e. day 7, promyelocytes). According with Proton Leak (PL) values, AML blasts can be grouped in two well defined populations. The AML group with blasts presenting high PL or high basal OXPHOS plus high SRC levels had shorter overall survival time and significantly overexpressed myeloid cell leukemia 1 (MCL1) protein. We demonstrate that MCL1 directly binds to Hexokinase 2 (HK2) on the outer mitochondrial membrane (OMM). Overall, these results suggest that high PL and high SRC plus high basal OXPHOS levels at disease onset, arguably with the concourse of MCL1/HK2 action, are significantly linked with shorter overall survival time in AML. Our data describe a new function for MCL1 protein in AMLs’ cells: by forming a complex with HK2, MCL1 co-localizes to VDAC on the OMM, thus inducing glycolysis and OXPHOS, ultimately conferring metabolic plasticity and promoting resistance to therapy.

我们使用 Seahorse XF Agilent 将诊断时分离的原发性 AML 母细胞的代谢与正常造血成熟祖细胞的代谢进行比较，从而描述不同急性髓系白血病 (AML) 的代谢背景。与造血前体细胞（即第 7 天的早幼粒细胞）相比，白血病细胞具有较低的备用呼吸 (SRC) 和糖酵解能力。根据质子泄漏 (PL) 值，AML 母细胞可分为两个明确定义的群体。具有高 PL 或高基础 OXPHOS 加上高 SRC 水平的原始细胞的 AML 组的总生存时间较短，并且显着过度表达骨髓细胞白血病 1 (MCL1) 蛋白。我们证明 MCL1 直接与线粒体外膜 (OMM) 上的己糖激酶 2 (HK2) 结合。总体而言，这些结果表明，疾病发作时的高 PL 和高 SRC 加上高基础 OXPHOS 水平（可能与 MCL1/HK2 作用同时发生）与 AML 的总生存期较短显着相关。我们的数据描述了 AML 细胞中 MCL1 蛋白的新功能：通过与 HK2 形成复合物，MCL1 共定位于 OMM 上的 VDAC，从而诱导糖酵解和 OXPHOS，最终赋予代谢可塑性并促进对治疗的抵抗。