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Transient Receptor Potential Melastatin Subfamily Member 4 (TRPM4) has been demonstrated to be aberrantly expressed in several cancers but seldom reported in acute leukemia. Based on database mining and validated experiments, our present data show that TRPM4 is selectively overexpressed in AML patients and cell lines with the MLL gene rearrangement. We analyzed the correlation between TRPM4 expression and clinical parameters in a validated cohort of AML patients. Increased TRPM4 expression was associated with significant leukocytosis (p =.028), M4/M5 subtype (p =.000), FLT3-ITD mutation (p =.034), MLL status (p =.007) and a higher risk stratification (p =.001). Knockdown of TRPM4 mediated by siRNA impaired proliferation and arrested the cell cycle at the G0/G1 phase in MLL -rearranged leukemia cells. We suggested that TRPM4 may be involved in the pathogenesis of MLL -rearranged leukemia through regulating the AKT/GLI1/Cyclin D1 pathway. The transcription factor HOXA9 was found to be responsible for upregulation of TRPM4 expression by binding to its promoter. In conclusion, TRPM4 is overexpressed in MLL -rearranged AML and blockade of TRPM4 may be an alternative therapeutic approach in AML patients with high TRPM4 expression. • Significantly increased TRPM4 was found in MLL -AML patients and cell lines. • TRPM4 silencing inhibited proliferation and cell cycle progression in MLL -rearranged AML through AKT/GLI1/ Cyclin D1 pathway. • HOXA9 was found to be involved in the overexpression of TRPM4. [ABSTRACT FROM AUTHOR]