转录因子Forkhead box P1（FOXP1）属于与FOXOs相同的蛋白家族，这些蛋白以抑制氧化应激而被广泛认为是小鼠造血干细胞的调节因子。FOXP1和FOXOs在细胞环境不同的情况下可以发挥相反或相似的作用；它们可以相互调控表达。我们之前的研究表明FOXP1对正常人类HSP和急性髓性白血病（AML）细胞的生长有贡献。在这里，我们研究了FOXP1在人类HSPCs和AML细胞氧化应激防御中的作用。FOXP1表达水平与无细胞遗传学异常（CN）AML患者的预后不良有关。FOXP1敲低增强了人类已定向的CD34+CD38+但不是富含干细胞的CD34+CD38- HSPCs和AML细胞体内的超氧阴离子水平。它触发了NRF2活性和细胞氧化应激的增加。FOXP1在这些细胞中没有影响FOXO1/3/4的表达；FOXOs的遗传和药物抑制没有改变人类HSPCs和AML细胞的超氧阴离子水平。同时，FOXP1的抗氧化活性与超氧化物歧化酶（SOD）1-2或过氧化氢酶的表达变化无关。相反，FOXP1通过稳定SIRT1蛋白，上调了压力传感器SIRT1的表达。FOXP1的丧失使AML细胞对化疗更加敏感。总体而言，本研究确定了FOXP1作为髓系前体细胞氧化应激的新保护措施，它与FOXOs无关，而是通过SIRT1发挥作用，并促进AML药物抗性。它提出了FOXP1表达/活性作为克服AML HSPCs药物抵抗的有希望的靶点。版权所有©2023美国血液学会。

Transcription factor Forkhead box P1 (FOXP1) belongs to the same protein family as the FOXOs that are well-known regulators of murine hematopoietic stem progenitor cell (HSPC) maintenance by dampening oxidative stress. FOXP1 and FOXOs can play opposite or similar roles depending on cell context; they can cross-regulate each other's expression. In a previous study, we have shown that FOXP1 contributes to normal human HSP and acute myeloid leukemia (AML) cell growth. Here we investigated the role of FOXP1 in HSPCs and AML cell oxidative stress defense in human context. FOXP1 expression level was associated with inferior survival outcome of cytogenetically normal (CN) AML patients. FOXP1 knockdown enhanced superoxide anion levels of human committed CD34+CD38+ but not stem cell-enriched CD34+CD38- HSPCs, and AML cells in vitro. It triggered enhanced NRF2 activity and increased cell oxidative stress. FOXP1 had no impact on FOXO1/3/4 expression in these cells; genetic and pharmacological inhibition of FOXOs did not change superoxide anion levels of human HSPCs and AML cells. Also, FOXP1 antioxidant activity was independent of superoxide dismutase (SOD)1-2 or catalase expression changes. Instead, FOXP1 upregulated expression of the stress sensor SIRT1 by stabilizing SIRT1 protein. FOXP1 loss sensitized AML cells to chemotherapy. Altogether, this study identified FOXP1 as a new safeguard against myeloid progenitor oxidative stress, which works independently of FOXOs but through SIRT1, and contributes to AML chemoresistance. It proposes FOXP1 expression/activity as a promising target to overcome drug-resistance of AML HSPCs.Copyright © 2023 American Society of Hematology.