FOXP1 regulates oxidative stress, SIRT1 expression, and resistance to chemotherapies in acute myeloid leukemia cells.

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.