LEDGF/p75 Mediates Chemoresistance in Leukemia in a Context Dependent Manner

Lens epithelium-derived growth factor p75 (LEDGF/p75), also known as PSIP1, is a chromatin-associated protein involved in transcriptional regulation, stress adaptation, and leukemia maintenance. In KMT2A-rearranged leukemia (KMT2A-r), LEDGF/p75 tethers KMT2A fusion complex to chromatin and is essential for leukemogenesis. However, its contribution to therapy resistance across different leukemic subtypes remains poorly defined. Here, we investigated the role of LEDGF/p75 in therapy response across leukemia models with diverse genetic backgrounds. We show that LEDGF/p75 depletion sensitizes KMT2A-r T cell acute lymphoblastic leukemia (T-ALL) cells to cytarabine, whereas depletion of LEDGF/p75 in KMT2A-r B cell acute lymphoblastic leukemia (B-ALL) cells protects against cytarabine-induced apoptosis, highlighting context-specific functions of LEDGF/p75. Notably, in chronic myeloid leukemia (CML) cells harboring BCR-ABL fusion, loss of LEDGF/p75 increases sensitivity to vincristine and BCR-ABL inhibitors. Mechanistically, transcriptomic and protein analysis revealed that LEDGF/p75 depletion in CML cells is associated with reduced JAK2-STAT5 signaling, upregulation of apoptotic transcriptional programs, and suppression of proliferation and drug resistance gene signatures. Together, these findings demonstrate a context-dependent role of LEDGF/p75 in leukemic therapy resistance and identify LEDGF/p75 as a therapeutic vulnerability that could be exploited to enhance treatment sensitivity in selected leukemic subtypes, including BCR-ABL-positive CML.