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How to resist Notch-targeted T-leukemia therapy: Lineage- and MYC enhancer switch

Marc Bayer1, Rudolf Grosschedl1

  • 1Max Planck Institute of Immunobiology and Epigenetics, 79108 Freiburg, Germany.

Molecular Cell
|March 4, 2022
PubMed

Insights

Gain-of-function NOTCH1 mutations drive T-ALL. In resistant T-ALL cells, EBF1 activation causes a T-to-B lineage shift, maintaining MYC expression without Notch signaling.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Biology

Background:

  • Gain-of-function NOTCH1 mutations are key drivers of T-cell acute lymphoblastic leukemia (T-ALL).
  • Notch signaling is crucial for T-ALL pathogenesis and a target for therapy.
  • Therapy resistance remains a significant challenge in T-ALL treatment.

Purpose of the Study:

  • To investigate the mechanisms underlying Notch-targeted therapy resistance in T-ALL.
  • To identify alternative pathways that maintain oncogenic MYC expression in resistant T-ALL cells.

Main Methods:

  • Analysis of gene expression and signaling pathways in T-ALL cell lines and patient samples.
  • Investigating the role of EBF1 in T-ALL cell differentiation and survival.

Main Results:

  • Notch-targeted therapy-resistant T-ALL cells activate the transcription factor EBF1.
  • EBF1 promotes a T-cell to B-cell lineage switch.
  • EBF1 maintains oncogenic MYC expression independently of Notch signaling in resistant cells.

Conclusions:

  • EBF1 activation is a critical mechanism for Notch-independent survival and proliferation in resistant T-ALL.
  • Targeting EBF1 may represent a novel therapeutic strategy for overcoming Notch-targeted therapy resistance in T-ALL.

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