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December 8, 2025Blood

The KMT2A-PTD oncoprotein depends on ENL but not menin to drive AML gene expression

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Authors

WBWallace BourgeoisYWYanhe WenJPJennifer A. Perry

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Overview

Findings indicate KMT2A-PTD leukemia shows intrinsic resistance to inhibitors, suggesting new treatment avenues via differentiation.

Key Points

  • This research aims to understand the mechanisms driving gene expression in KMT2A-PTD mediated AML.
  • Investigated KMT2A-PTD and KMT2A-WT in EOL-1 cells using PROTACs to assess protein degradation effects.
  • Defined target genes through genome-wide chromatin binding site analysis and nascent RNA changes.
  • Explored effects of ENL and AF9 YEATS inhibition on KMT2A-PTD functions and leukemia proliferation.
  • KMT2A-PTD is critical for leukemia growth, showing resistance to menin inhibitors.
  • YEATS inhibitors reduced leukemia burden in vivo by inducing differentiation.
  • Combination treatment of MI and YEATS inhibitors was synergistic in reducing leukemia proliferation.

Cite This Study

Bourgeois et al. (2025) studied this question.

synapsesocial.com/papers/693624d44fa91c937236d013https://doi.org/10.1182/blood-2025-321
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Also Consider

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

  1. 1Additional genetic targets are present in the majority of AML patients with NPM1, KMT2A or NUP98 aberrations potentially impacting combination therapy with menin inhibitors2025
  2. 2The role of the lysine histone methylase KMT2D in chronic myeloid leukemia2025 · 2 citations
  3. 3KMT2A::AF6 fusion protein localizes to PML nuclear bodies and undergoes ATO-induced degradation: A potential novel therapeutic approach for KMT2A::AF6-rearranged Acute Myeloid Leukemia2025
  4. 4HMGA1 chromatin regulators drive transcriptional networks governing cell cycle progression, immune escape, and menin-inhibitor resistance in KMT2A-r Acute Myeloid Leukemia2025
  5. 5A perturb-seq map of a differentiation hub reveals synergistic vulnerabilities in KMT2A-rearranged AML2025