SMARCA5 deficiency reprograms AKR1B1-mediated endogenous fructose metabolism to eradicate leukemia stem cells in acute myeloid leukemia

A significant variation in chromatin accessibility is an epigenetic feature in leukemia cells. However, the regulators and consequences of the chromatin accessibility variations in leukemia remain elusive. Here we identified SMARCA5, a core ATPase of the ISWI chromatin remodeling complex, as the primary regulator of chromatin accessibility in acute myeloid leukemia (AML) by CRISPR-Cas9 library screening. We found that SMARCA5 is required for self-renewal of leukemia stem cells and myeloid leukemogenesis. Mechanistically, SMARCA5 promotes the transcriptional activation of AKR1B1, an aldo/keto reductase, by recruiting transcription co-activator DDX5 and transcription factor SP1 to its promoter. Clinical sample analysis has shown that high expression of AKR1B1 predicts a poor prognosis in AML patients. Interestingly, AKR1B1-mediated endogenous fructose metabolism is reprogrammed by Smarca5 in AML. Overexpression of AKR1B1 rescued the leukemogenesis impaired by Smarca5 deficiency. Moreover, pharmacological inhibition of AKR1B1 displayed significant therapeutic effects in the AML patient-derived xenograft (PDX) mouse model. Thus, our findings link chromatin state dynamics regulated by SMARCA5 to AKR1B1-mediated endogenous fructose metabolism reprogramming, and uncover an essential role of AKR1B1 in AML, which may provide a therapeutic target for AML patients. Suppression of SMARCA5 by shRNA in Kasumi-1 cells, as well as the control cells were subjected to RNA-seq, ATAC-seq. Cut & Tag of SMARCA5 was performed with SMARCA5 antibody in Kasumi-1 cells and THP-1 cells, and rabbit IgG as the control.