Menin-MLL inhibitors enhance AP-1 transcription factor JUND activity in MLLr leukemic cells which contributes to tumorigenesis and therapy resistance (sampleIDs - EO241-EO252; MV-411 cell lines)

ABSTRACT: Background: MLL-rearranged (MLLr) acute myeloid leukemia (AML) and acute lymphoid leukemia (ALL) involve reciprocal oncogenic translocations of the KMT2A/KMT2B (MLL1/MLL2) gene on chromosome 11q23 with various translocation partner genes, which yields to chimeric MLL fusion proteins (MLL-FPs). Menin, the protein product of the MEN1 gene, is essential for the leukemogenic activity of MLL-FPs. Revumenib, a small-molecule inhibitor that selectively disrupts the menin-MLL interaction, has recently received FDA approval for clinical use for the treatment of adult and pediatric patients with relapsed or refractory MLLr acute leukemia. Notably, menin also interacts with the AP-1 transcription factor JUND through a conserved sequence identical to that required for MLL-FP binding. Despite this structural similarity, the impact of menin-MLL inhibitors on JUND function has remained unexplored. Results: In this study, we investigated the influence of menin-MLL inhibitors on JUND activity. Quantitative mass spectrometry analysis of MLLr leukemia cells treated with menin-MLL inhibitors demonstrated that they also disrupt menin-JUND protein interactions. Furthermore, CRISPR-mediated inactivation of JUND or pharmacological inhibition using JNK inhibitors synergistically enhanced the anti-leukemic effects of menin-MLL inhibitors, leading to reduced cell proliferation, cell cycle arrest and apoptosis. RNA sequencing and chromatin binding assays revealed that menin-MLL inhibitor treatment increases JUND chromatin occupancy, leading to upregulation of target gene expression and potentially contributing to the development of resistance to menin-MLL inhibitors. Mouse models engrafted with JUND-deficient leukemia cells exhibited reduced tumor burden compared to control mice engrafted with wild type leukemic cells. Conclusion: These findings suggest that targeting JUND activity may significantly enhance the efficacy of menin-MLL inhibitors towards MLLr leukemia cells.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Blood

SUBMITTER: Marc Timmers  

LAB HEAD: Marc Timmers

PROVIDER: PXD067825 | Pride | 2026-07-28

REPOSITORIES: Pride