Abstract

Long interspersed element-1 (LINE-1 or L1) is the only autonomous transposon in humans, and its mobilization varies across cancers. The regulation of LINE-1 expression and its impact on acute myeloid leukemia (AML) remain incompletely understood. Our previous work demonstrated that LINE-1 activation prevents AML development, prompting us to explore how LINE-1 repressors affect AML. Here we constructed a four-gene signature (LINE-1 repressors index, LRI) that effectively stratifies risk in AML patients. Further analysis identified microrchidia family CW-type zinc finger 2 (MORC2) as a key predictor of AML clinical outcomes within the LRI genes. MORC2 depletion significantly impairs leukemia cell proliferation, reduces tumor burden and attenuates AML progression. Mechanistically, MORC2 restricts LINE-1 activity in leukemia cells. Downregulation of MORC2 increases LINE-1 expression and retrotransposition, which in turn accumulates DNA damage and compromises the genomic stability required for leukemia cell proliferation. Collectively, these observations suggest that targeted inhibition of MORC2 to activate LINE-1 may represent a new therapeutic strategy for AML.