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December 8, 2025Blood1 citations

KMT2A-PTD Leukemia Drives Gene Expression via Chromatin Regulation and Treatment Strategies

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

Experimental models demonstrate that chromatin-bound KMT2A-PTD supports aberrant gene expression, suggesting effective treatment strategies.

Key Points

  • To analyze the role of KMT2A-PTD in acute myeloid leukemia and explore potential treatment strategies.
  • Utilized EOL-1 cell models with KMT2A-PTD tagged for protein degradation studies.
  • Assessed genome-wide chromatin binding and gene expression changes following targeted degradation.
  • Investigated resistance mechanisms to menin inhibitors and explored combination therapies with YEATS domain inhibitors.
  • KMT2A-PTD dependency was critical for leukemia cell growth and gene expression.
  • Resistance to menin inhibitors was linked to KMT2A-PTD chromatin retention and protein domain duplication.
  • Combination of menin and YEATS domain inhibitors showed synergistic effects and reduced leukemia burden in vivo.

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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