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December 8, 2025BloodOpen Access

MLLT1/3 targeted protein degradation as the best-in-class approach for targeting the super elongation complex (SEC) in acute leukemia, including menin inhibitor refractory disease

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Authors

GCGraham CraggsGFGillian FarnieMFMatthew Fawkes

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Overview

The study finds that MLLT-TPD drives degradation of oncogenes in acute leukemia, suggesting it may surpass menin inhibitors.

Key Points

  • To evaluate the effectiveness of MLLT1/3 targeted protein degradation (MLLT-TPD) in acute leukemia treatment.
  • Assessed MLLT1/3 degradation by JESS Simple Western and flow cytometry.
  • Measured MLLT target gene expression using qPCR.
  • Conducted RNAseq and CUT&Tag analyses to evaluate SEC-dependent biology.
  • Evaluated cell viability using CellTiter-Glo assay.
  • Tested MLLT-TPD in mouse xenograft models of AML.
  • Developed a selective MLLT-TPD that effectively degrades MLLT1.
  • MLLT-TPD leads to rapid decreases in SEC dependent gene transcription.
  • MLLT-TPD shows greater efficacy compared to menin inhibitors in multiple leukemia models.
  • Demonstrated activity against AML cells with menin inhibitor resistance mutations.

Cite This Study

Craggs et al. (2025) studied this question.

synapsesocial.com/papers/693624d44fa91c937236d00fhttps://doi.org/10.1182/blood-2025-320
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Also Consider

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  1. 1A first-in-class oral clinical candidate targeting MLLT1 and 3 degradation for the treatment of advanced AML and ALL including menin inhibitor resistant / refractory disease2025
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  3. 3The KMT2A-PTD oncoprotein depends on ENL but not menin to drive AML gene expression2025 · 1 citations
  4. 4Synergistic targeting of KMT2A-rearranged AML with combined LSD1 and menin inhibitors2025
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