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A niche driven mechanism determines response and a mutation-independent therapeutic approach for myeloid malignancies

Ioanna Mosialou1, Abdullah M Ali2, Rossella Labella3

  • 1Department of Physiology and Cellular Biophysics, College of Physicians and Surgeons, Columbia University Medical Center, New York, NY 10032, USA; Edward P. Evans for Myelodysplastic Syndromes at Columbia University Medical Center, New York, NY 10032, USA.

Cancer Cell
|March 28, 2025
PubMed

Insights

All-trans-retinoic acid (ATRA) therapy shows promise for myeloid cancers like myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). ATRA suppresses a key signaling pathway, inhibiting cancer growth and promoting differentiation, with improved outcomes in mice.

Area of Science:

  • Hematology
  • Oncology
  • Molecular Biology

Background:

  • Myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) are hematologic malignancies with limited treatment options.
  • Resistance to standard of care (SOC) and targeted therapies necessitates novel therapeutic strategies.

Purpose of the Study:

  • To investigate the role of β-catenin-JAG1 signaling in therapy response in MDS/AML.
  • To evaluate all-trans-retinoic acid (ATRA) as a therapeutic agent for myeloid malignancies.

Main Methods:

  • Analysis of β-catenin-JAG1 activation in osteoblastic cells of patients treated with ATRA.
  • Assessment of ATRA's effects on MDS/AML cell growth, survival, and differentiation in vitro and in vivo.
  • Evaluation of a human anti-JAG1 antibody in combination with ATRA.

Main Results:

  • Therapy responsiveness correlated with β-catenin-JAG1 activation in osteoblastic cells.
  • ATRA suppressed β-catenin activity, inhibited MDS/AML cell growth and survival, and promoted differentiation.
  • ATRA treatment improved disease outcomes in leukemic mice with a favorable safety profile.
  • An anti-JAG1 antibody enhanced ATRA efficacy in preclinical models.

Conclusions:

  • β-catenin activation serves as a mechanistic biomarker for ATRA response in myeloid malignancies.
  • ATRA repurposing holds potential for treating MDS/AML, possibly reducing relapse risk.
  • This pathway modulation may extend to other cancer types.
Keywords:
AMLATRAMDSanti-JAGGED1b-cateninbone marrow microenvironmenthumanized antibodymyeloid malignanciestherapy

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