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December 8, 2025BloodOpen Access

Targeting BRD9 in KMT2A-rearranged Acute Myeloid Leukemia to circumvent MEN1 inhibitor resistance

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Authors

DWDaniela V. Wenge

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Overview

The study shows that targeting BRD9 and IRF8 improves outcomes in KMT2A AML, suggesting new treatment strategies against MEN1 resistance.

Key Points

  • This research aims to explore the role of BRD9 in KMT2A-rearranged acute myeloid leukemia and its potential as a therapeutic target.
  • Investigated BRD9 functions in AML cell lines and primary samples using a BRD9 degrader and MEN1 inhibitor.
  • Applied MTT and CellTiter-Glo assays to measure cell viability and flow cytometry for myeloid differentiation.
  • Utilized ATAC-seq and RNA-seq to analyze chromatin accessibility and transcriptomic changes.
  • Transduced IRF8 and MYC expression into MOLM-13 to assess effects on myeloid differentiation.
  • BRD9 loss induced growth defects and myeloid differentiation in KMT2Ar cell lines.
  • Transcriptomic analysis revealed downregulation of IRF8 and MYC following BRD9 depletion.
  • Primary AML samples exhibited varied sensitivity to BRD9 depletion based on IRF8 expression levels.
  • BRD9 and MEN1 were found to independently regulate the TF addiction pathway and KMT2A/MEN1 pathway.

Cite This Study

Daniela V. Wenge (2025) studied this question.

synapsesocial.com/papers/69362f604fa91c937236dcb6https://doi.org/10.1182/blood-2025-1463
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Also Consider

Synapse has enriched 5 closely related papers on similar clinical questions. Consider them for comparative context:

  1. 1The KMT2A-PTD oncoprotein depends on ENL but not menin to drive AML gene expression2025 · 1 citations
  2. 2Protein degradation of MYC/GSPT1 combined with menin inhibition overcomes resistance to menin inhibition in KMT2A-rearranged Acute Myeloid Leukemia2025 · 1 citations
  3. 3Targeting the Menin– <scp>KMT2A</scp> Axis in Acute Leukemia: From Epigenetic Dependency to Clinical Translation2026 · 1 citations
  4. 4Epigenetic Regulation of Non-canonical Menin Targets Modulates Menin Inhibitor Response in Acute Myeloid Leukemia2024 · 47 citations
  5. 5Abstract 1227: Novel combination therapies to overcome non-genetic/adaptive menin inhibitor resistance in AML with MLL1r or mtNPM12024