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Spatiotemporal gene expression is regulated by the SNF2 family of ATPases that remodel chromatin, among which helicase lymphoid-specific (HELLS) play an essential role in DNA-templated processes. Analysis from cancer databases revealed HELLS upregulation in several cancers, including acute myeloid leukemia (AML). Using an in vitro myeloid differentiation model, we found that HELLS deficiency promotes myeloid differentiation, apoptosis, cell-cycle arrest, and chromatin instability. Furthermore, HELLS deficiency enhanced myeloid differentiation and apoptosis in HL-60 cells when treated with chemotherapy drugs, including 5-azacytidine, cytarabine, and doxorubicin. Epigenetically, loss of HELLS reduced active histone mark (H3K4me3) and enhanced repressive promoter (H3K27me3), active enhancer (H3K27ac) marks, and chromatin accessibility. Transcriptomic analysis of BeatAML data and bioinformatics analysis revealed that HELLS upregulation is associated with adverse prognosis, as defined by the ELN-2017 classification, and significantly poorer survival. Classification of AML patients into HELLS and HELLS gene-expression groups showed that lower HELLS expression was associated with a favorable prognosis and improved remission. HELLS upregulation was positively and negatively associated with leukemic stem/progenitor cell (LSPC) markers and myeloid lineage markers, respectively. Ex vivo validation in AML patient-derived LSPCs demonstrated that HELLS deficiency reduces leukemic marker burden (CD123 and TIM-3) and increases apoptosis. Overall, we show HELLS upregulation drives leukemogenesis with poor outcomes, highlighting its potential as a prognostic marker and therapeutic target in AML.