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

Ioanna Mosialou¹, Abdullah M Ali², Rossella Labella³, Brygida Bisikirska³, Alvaro Cuesta-Dominguez³, Paraskevi Vgenopoulou³, Ismarc Reyes³, Sanjana M Rao³, Anqi Wang⁴, Na Luo³, Marta Galan-Diez³, Junfei Zhao⁴, Brian J Chernak⁵, Jan Philipp Bewersdorf⁶, Kazuya Fukasawa³, Jiayu Su⁴, Jason Higa⁷, Rachel A Adams⁷, Adam L Corper⁷, Sergey Pampou⁸, Catherine M Woods⁷, Xiaomin Fan⁷, Roshan P Shah⁹, Julie Feldstein⁶, Na Liu¹⁰, Cui Liang¹⁰, Maël Heiblig¹¹, Steven Kornblau¹², Guillermo Garcia-Manero¹², Ellin Berman⁶, Joseph G Jurcic⁵, Raul Rabadan¹³, Azra Raza¹⁴, Stavroula Kousteni¹⁵

Affiliations

¹ Department 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. Electronic address: im2333@cumc.columbia.edu.
² Edward P. Evans for Myelodysplastic Syndromes at Columbia University Medical Center, New York, NY 10032, USA; Herbert Irving Comprehensive Cancer Center (HICCC), Columbia University, New York, NY 10032, USA; Myelodysplastic Syndromes Center, Columbia University, New York, NY 10032, USA.
³ Department of Physiology and Cellular Biophysics, College of Physicians and Surgeons, Columbia University Medical Center, New York, NY 10032, USA.
⁴ Program for Mathematical Genomics, Department of Systems Biology, Columbia University Medical Center, New York, NY 10032, USA.
⁵ Department of Med Hematology & Oncology, Columbia University Medical Center, New York, NY 10032, USA.
⁶ Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
⁷ AvantGen Inc, San Diego, CA 92121, USA.
⁸ Department of Systems Biology, Columbia University Medical Center, New York, NY 10032, USA.
⁹ Department of Orthopedic Surgery, Columbia University Medical Center, New York, NY 10032, USA.
¹⁰ Department of Hematology, Institute of Hematology, First Affiliated Hospital, Naval Medical University, Shanghai 200433, China.
¹¹ Department of Hematology Centre Hospitalier Lyon Sud, 69495 Lyon, France.
¹² Department of Leukemia, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
¹³ Edward P. Evans for Myelodysplastic Syndromes at Columbia University Medical Center, New York, NY 10032, USA; Program for Mathematical Genomics, Department of Systems Biology, Columbia University Medical Center, New York, NY 10032, USA.
¹⁴ Edward P. Evans for Myelodysplastic Syndromes at Columbia University Medical Center, New York, NY 10032, USA; Herbert Irving Comprehensive Cancer Center (HICCC), Columbia University, New York, NY 10032, USA; Myelodysplastic Syndromes Center, Columbia University, New York, NY 10032, USA; Department of Med Hematology & Oncology, Columbia University Medical Center, New York, NY 10032, USA.
¹⁵ Department 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; Herbert Irving Comprehensive Cancer Center (HICCC), Columbia University, New York, NY 10032, USA; Columbia Stem Cell Initiative, Columbia University, New York, NY 10032, USA. Electronic address: sk2836@cumc.columbia.edu.

PMID: 40154481
PMCID: PMC12151774 (available on 2026-06-09)
DOI: 10.1016/j.ccell.2025.03.007

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

Ioanna Mosialou et al. Cancer Cell. 2025.

. 2025 Jun 9;43(6):1007-1024.e13.

doi: 10.1016/j.ccell.2025.03.007. Epub 2025 Mar 27.

Authors

Affiliations

¹ Department 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. Electronic address: im2333@cumc.columbia.edu.
² Edward P. Evans for Myelodysplastic Syndromes at Columbia University Medical Center, New York, NY 10032, USA; Herbert Irving Comprehensive Cancer Center (HICCC), Columbia University, New York, NY 10032, USA; Myelodysplastic Syndromes Center, Columbia University, New York, NY 10032, USA.
³ Department of Physiology and Cellular Biophysics, College of Physicians and Surgeons, Columbia University Medical Center, New York, NY 10032, USA.
⁴ Program for Mathematical Genomics, Department of Systems Biology, Columbia University Medical Center, New York, NY 10032, USA.
⁵ Department of Med Hematology & Oncology, Columbia University Medical Center, New York, NY 10032, USA.
⁶ Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
⁷ AvantGen Inc, San Diego, CA 92121, USA.
⁸ Department of Systems Biology, Columbia University Medical Center, New York, NY 10032, USA.
⁹ Department of Orthopedic Surgery, Columbia University Medical Center, New York, NY 10032, USA.
¹⁰ Department of Hematology, Institute of Hematology, First Affiliated Hospital, Naval Medical University, Shanghai 200433, China.
¹¹ Department of Hematology Centre Hospitalier Lyon Sud, 69495 Lyon, France.
¹² Department of Leukemia, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
¹³ Edward P. Evans for Myelodysplastic Syndromes at Columbia University Medical Center, New York, NY 10032, USA; Program for Mathematical Genomics, Department of Systems Biology, Columbia University Medical Center, New York, NY 10032, USA.
¹⁴ Edward P. Evans for Myelodysplastic Syndromes at Columbia University Medical Center, New York, NY 10032, USA; Herbert Irving Comprehensive Cancer Center (HICCC), Columbia University, New York, NY 10032, USA; Myelodysplastic Syndromes Center, Columbia University, New York, NY 10032, USA; Department of Med Hematology & Oncology, Columbia University Medical Center, New York, NY 10032, USA.
¹⁵ Department 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; Herbert Irving Comprehensive Cancer Center (HICCC), Columbia University, New York, NY 10032, USA; Columbia Stem Cell Initiative, Columbia University, New York, NY 10032, USA. Electronic address: sk2836@cumc.columbia.edu.

PMID: 40154481
PMCID: PMC12151774 (available on 2026-06-09)
DOI: 10.1016/j.ccell.2025.03.007

Abstract

Myeloid cancers such as myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) remain resistant to standard of care (SOC) and targeted therapies. In this study, we demonstrate that responsiveness to therapy is associated with activation of β-catenin-JAG1 in osteoblastic cells of patients treated with all-trans-retinoic acid (ATRA). ATRA suppresses β-catenin activity in patients and leukemic mice. Consequently, it inhibits the growth and survival of MDS/AML cells from patients with active β-catenin-JAG1 signaling and promotes their differentiation. This occurs independently of cytogenetics and mutational profile. ATRA also improves disease outcome in mice with no evidence of relapse and a superior safety profile to SOC. A human anti-JAG1 antibody improves efficacy in leukemic mice and patient-derived MDS/AML cells. β-catenin activation provides an explanation for the differential response to ATRA and a mechanistic biomarker for ATRA repurposing in myeloid malignancies, potentially evading relapse and extending across a broad range of cancers.

Keywords: AML; ATRA; MDS; anti-JAGGED1; b-catenin; bone marrow microenvironment; humanized antibody; myeloid malignancies; therapy.

PubMed Disclaimer

Conflict of interest statement

Declaration of interests S. Kousteni is inventor on the issued patent 14/760,026 to the Trustees of Columbia University in the City of New York related to ATRA and anti-Jagged1 work. S. Kousteni, A.R., A.M.A., and I.M. are co-inventors on the pending patent application PCT/US2014/011295 filed by the Trustees of Columbia University in the City of New York related to the ATRA and anti-Jagged1 work. X.F and SK are inventors on the pending patent application U.S. Serial No. 63/330,294 filed by AvantGen for JAGGED1 binding agents and uses thereof.

References

1. Kantarjian H, Kadia T, DiNardo C, Daver N, Borthakur G, Jabbour E, Garcia-Manero G, Konopleva M, and Ravandi F (2021). Acute myeloid leukemia: current progress and future directions. Blood Cancer J 11, 41. 10.1038/s41408-021-00425-3. - DOI - PMC - PubMed
1. Klepin HD, Rao AV, and Pardee TS (2014). Acute myeloid leukemia and myelodysplastic syndromes in older adults. J Clin Oncol 32, 2541–2552. 10.1200/JCO.2014.55.1564. - DOI - PMC - PubMed
1. Hellström-Lindberg E, Tobiasson M, and Greenberg P (2020). Myelodysplastic syndromes: moving towards personalized management. Haematologica 105, 1765–1779. 10.3324/haematol.2020.248955. - DOI - PMC - PubMed
1. Jaiswal S, Fontanillas P, Flannick J, Manning A, Grauman PV, Mar BG, Lindsley RC, Mermel CH, Burtt N, Chavez A, et al. (2014). Age-related clonal hematopoiesis associated with adverse outcomes. N Engl J Med 371, 2488–2498. 10.1056/NEJMoa1408617. - DOI - PMC - PubMed
1. Xie M, Lu C, Wang J, McLellan MD, Johnson KJ, Wendl MC, McMichael JF, Schmidt HK, Yellapantula V, Miller CA, et al. (2014). Age-related mutations associated with clonal hematopoietic expansion and malignancies. Nat Med 20, 1472–1478. 10.1038/nm.3733. - DOI - PMC - PubMed

MeSH terms

Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions

Substances

Actions
Actions
Actions
Actions

Grants and funding

LinkOut - more resources

Full Text Sources
- Elsevier Science
Medical
- MedlinePlus Health Information
Molecular Biology Databases
- Mouse Genome Informatics (MGI)
Research Materials
- NCI CPTC Antibody Characterization Program
Miscellaneous
- NCI CPTAC Assay Portal

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

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

Affiliations

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

Authors

Affiliations

Abstract

Conflict of interest statement

References

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources

Medical

Molecular Biology Databases

Research Materials

Miscellaneous