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.

Autosomal dominant STAT1 gain-of-function (GOF) is an inborn error of immunity characterized by chronic mucocutaneous candidiasis and variable immune dysregulation. JAK inhibitors are a promising therapy, but their efficacy in STAT1 GOF remains variable. We longitudinally evaluated the clinical and molecular impact of JAK inhibitors in two STAT1 GOF patients, harboring p.R321S and p.T385M mutations, using Cellular Indexing of Transcriptomes and Epitopes by sequencing, flow cytometry, cytokine measurement, and allele-specific expression analysis in peripheral blood mononuclear cells and serum. Rapid yet incomplete immune reconstitution was observed as early as 1 week after treatment initiation. T cells rebalanced to a more homeostatic status and TCR repertoire diversity increased rapidly. However, some immune defects remained, including natural killer deficiency in one patient. The pronounced transcriptional dysregulation in monocytes was not explained by an unbalanced mutant STAT1 expression but improved with JAK-inhibitor treatment. JAK inhibitors provided significant clinical and immunological benefits to STAT1 GOF patients but did not fully restore immune homeostasis. These findings highlight the therapeutic potential and limitations of JAK inhibitors in STAT1 GOF.