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December 8, 2025Blood

Momelotinib-mediated transcriptional reprogramming induces synthetic lethal interaction with calcineurin-NFAT signaling

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Authors

MKMeenu KesarwaniZKZachary KincaidJSJoshua Schwieterman

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Overview

Functional studies reveal synthetic lethal interaction between momelotinib and calcineurin-NFAT signaling in AML, suggesting novel treatment strategies.

Key Points

  • Explore the therapeutic effects of momelotinib and calcineurin inhibitors in acute myeloid leukemia.
  • Performed whole genome CRISPR-Cas9 dropout screen
  • Evaluated the effects of momelotinib and calcineurin inhibitors in murine AML models
  • Analysed gene dependencies and transcriptional activity using RNA-seq, ATAC-seq, and CUT&RUN profiling.
  • Combination therapy showed curative responses in murine AML models
  • Momelotinib treatment uniquely depleted genes involved in cytokine signaling and calcineurin-NFAT signaling.
  • Induced dependencies on calcineurin-NFAT signaling confirmed as necessary for survival.

Cite This Study

Kesarwani et al. (2025) studied this question.

synapsesocial.com/papers/69362f714fa91c937236e199https://doi.org/10.1182/blood-2025-756
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Also Consider

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

  1. 1Negative feedback regulation of nfkb, MAPK, and JAK-STAT drives adaptive resistance to gilteritinib in AML2025
  2. 2Enhanced antileukemic activity of momelotinib in combination with venetoclax and azacitidine compared to gilteritinib-based combination2025
  3. 3Discovery of drug combinations with momelotinib to improve myelofibrosis outcomes2025
  4. 4Abstract 5870: Momelotinib: Unique polypharmacology and novel combination strategies for myelofibrosis and beyond2026
  5. 5Momelotinib's unique polypharmacology supports indication expansion beyond myelofibrosis2025