Abstract 3108: LEDGF/p75 drives chemoresistance in CML via JAK/STAT pathway modulation

Abstract Lens Epithelium Derived Growth Factor/p75 (LEDGF/p75,PSIP1) is a H3K36me2/3 reader implicated in several malignancies. Within the MLL/KMT2A fusion complex, it tethers the fusion protein to chromatin. KMT2A rearrangement (KMT2A-r) occurs in ∼10% of acute leukemia patients and is associated with poor prognosis due to relapse and chemoresistance. Our lab has shown that LEDGF/p75 is essential for KMT2A-r leukemogenesis but dispensable for hematopoiesis. High LEDGF/p75 levels have been linked to drug resistance in AML blasts, prostate and breast cancer. As a dependency factor in KMT2A-r leukemia, LEDGF/p75 is an attractive therapeutic target and a potential component of combinatorial strategies for LEDGF/p75 driven chemoresistance cancers. However, the leukemic subtypes dependent on LEDGF/p75 remains unclear. We previously showed that LEDGF/p75 depletion sensitizes KMT2A-r AML cells to cytarabine via the sphingosine-1 pathway. Here, we aimed to assess the role of LEDGF/p75 in therapy resistance across multiple leukemia models. Stable LEDGF/p75 knockdown (LEDGF/p75 KD) cell lines were generated using miRNA-expressing vectors, and more than ten leukemia cell lines were screened for LEDGF/p75 dependent chemoresistance. In KMT2A-wild-type (WT) AML cell lines U-937 and Kasumi-1, LEDGF/p75 depletion did not alter cytarabine sensitivity and the same trend was observed in WT T-ALL cell lines Jurkat and SupT-1. However, in the KMT2A-r T-ALL cell line, Karpas-45, LEDGF/p75 KD significantly sensitized the cells to cytarabine (IC50 Karpas Mock/KD: 76.32 ± 8.32 μM / 53.75 ± 12.46 μM). Unexpectedly, LEDGF/p75 KD in SEM cells (B-ALL, KMT2A-AF4) increased proliferation and reduced apoptosis upon cytarabine treatment (IC50 SEM Mock/KD: 0.12 ± 0.02 μM / 0.53 ± 0.06 μM). The latter was accompanied by a lower level of caspase3. Interestingly, LEDGF/p75 KD in two WT KMT2A CML cell lines, K-562 and JUR-MK1, led to a significant reduction in proliferation upon vincristine treatment (IC50 K-562 Mock/KD: 2.61 ± 0.10 nM / 0.81 ± 0.09 nM and IC50 JUR-MK1 Mock/KD: 3.93 ± 0.35 nM / 2.37 ± 0.30 nM) and increased apoptosis with elevated caspase3. Treatment of K-562 cells with BCR-ABL inhibitors Imatinib and Ponatinib also showed decreased proliferation upon LEDGF/p75 depletion. RNA-seq analysis of LEDGF/p75 KD K-562 and JUR-MK1 cells showed that LEDGF/p75 loss affects pathways associated with hematopoietic cell differentiation and immune response regulation. Anti apoptotic genes such as BCL-XL and BCL2A1 were downregulated, along with STAT5 and STAT2, key players in the JAK/STAT pathway. Western blotting confirmed reduced total and activated STAT5 in LEDGF/p75 depleted CML cells. Taken together, our result indicates that the role of LEDGF/p75 in therapy resistance is context dependent and varies across leukemic subtypes. We identify a previously unknown function of LEDGF/p75 in mediating drug resistance in CML cells acting through the JAK/STAT Pathway. Citation Format: Thatcher Akele, Cecilia Iglesias-Herrero, Frauke Christ, Zeger Debyser. LEDGF/p75 drives chemoresistance in CML via JAK/STAT pathway modulation abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 3108.