患有 inv(16) 的急性髓系白血病 (AML) 通常具有良好的预后。然而，高达 40% 的患者最终会出现疾病复发。在此，我们剖析了 inv(16) AML 的基因组和转录组谱，以确定潜在的预后标志物和治疗漏洞。来自 222 个诊断样本（包括 44 名复发/难治性患者）的测序数据显示，中位数为 1 个伴随的额外突变，与白血病发生中的 inv(16) 相配合。值得注意的是，与其他队列相比，除了复发/难治性组的突变负担增加之外，经历初次诱导失败或复发的患者在诊断时的突变情况没有显着差异。未配对的诊断 (n=7) 和复发 (n=6) 样本的 RNA-Seq 可以确定氧化磷酸化 (OXPHOS) 是复发时最显着下调的途径之一。考虑到 OXPHOS 可以被 Venetoclax/阿扎胞苷组合靶向，我们探讨了其对 inv(16) 细胞系 ME-1 的生物学效应，但在细胞死亡方面比单独使用阿扎胞苷没有额外的优势。为了增强 Venetoclax 的疗效，我们测试了二甲双胍作为一种潜在药物的体外作用，该药物能够通过抑制线粒体转移来增强 AML 细胞的化疗敏感性。通过用这种组合挑战 ME-1，我们观察到显着的协同相互作用，至少类似于 Venetoclax/Azacitidine。总之，我们通过 inv(16) 确定了 AML 复发时氧化磷酸化 (OXPHOS) 的表达下调，并探索了二甲双胍作为增强这种情况下化疗敏感性的潜在药物的体外效果。版权所有 © 2024。由 Elsevier 出版有限公司

Acute myeloid leukemia (AML) with inv(16) is typically associated with a favourable prognosis. However, up to 40 % of patients will eventually experience disease relapse. Herein, we dissected the genomic and transcriptomic profile of inv(16) AML to identify potential prognostic markers and therapeutic vulnerabilities. Sequencing data from 222 diagnostic samples, including 44 relapse/refractory patients, revealed a median of 1 concomitant additional mutation, cooperating with inv(16) in leukemogenesis. Notably, the mutational landscape at diagnosis did not differ significantly between patients experiencing primary induction failure or relapse when compared to the rest of the cohort, except for an increase in the mutational burden in the relapse/refractory group. RNA-Seq of unpaired diagnostic(n=7) and relapse(n=6) samples allowed the identification of oxidative phosphorylation (OXPHOS) as one of the most significantly downregulated pathways at relapse. Considering that OXPHOS could be targeted by Venetoclax/Azacitidine combination, we explored its biological effects on an inv(16) cell-line ME-1, but there was no additional advantage in terms of cell death over Azacitidine alone. To enhance Venetoclax efficacy, we tested in vitro effects of Metformin as a potential drug able to enhance chemosensitivity of AML cells by inhibiting the mitochondrial transfer. By challenging ME-1 with this combination, we observed a significant synergistic interaction at least similar to that of Venetoclax/Azacitidine. In conclusions, we identified a downregulated expression of oxidative phosphorylation (OXPHOS) at relapse in AML with inv(16), and explored the in vitro effects of metformin as a potential drug to enhance chemosensitivity in this setting.Copyright © 2024. Published by Elsevier Ltd.