A niche driven mechanism determines response and a mutation-independent therapeutic approach for myeloid malignancies Journal Article
| Authors: | Mosialou, I.; Ali, A. M.; Labella, R.; Bisikirska, B.; Cuesta-Dominguez, A.; Vgenopoulou, P.; Reyes, I.; Rao, S. M.; Wang, A.; Luo, N.; Galan-Diez, M.; Zhao, J.; Chernak, B. J.; Bewersdorf, J. P.; Fukasawa, K.; Su, J.; Higa, J.; Adams, R. A.; Corper, A. L.; Pampou, S.; Woods, C. M.; Fan, X.; Shah, R. P.; Feldstein, J.; Liu, N.; Liang, C.; Heiblig, M.; Kornblau, S.; Garcia-Manero, G.; Berman, E.; Jurcic, J. G.; Rabadan, R.; Raza, A.; Kousteni, S. |
| Article Title: | A niche driven mechanism determines response and a mutation-independent therapeutic approach for myeloid malignancies |
| 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. © 2025 Elsevier Inc. |
| Keywords: | signal transduction; controlled study; treatment response; gene mutation; genetics; mutation; leukemia, myeloid, acute; nonhuman; antineoplastic agents; antineoplastic agent; mouse; animal; metabolism; animals; mice; animal experiment; animal model; cytogenetics; cell differentiation; drug effect; drug screening; pathology; xenograft model antitumor assays; cell line, tumor; health care quality; myelodysplastic syndrome; cancer cell; leukemia cell; tumor cell line; upregulation; clinical effectiveness; kaplan meier method; drug therapy; beta catenin; retinoic acid; ctnnb1 protein, human; therapy; myelodysplastic syndromes; osteoblast; aml; mds; tretinoin; acute myeloid leukemia; myeloid malignancies; atra; b-catenin; humanized antibody; bone marrow microenvironment; humans; human; male; article; protein jagged 1; anti-jagged1 |
| Journal Title: | Cancer Cell |
| Volume: | 43 |
| Issue: | 6 |
| ISSN: | 1535-6108 |
| Publisher: | Cell Press |
| Date Published: | 2025-01-01 |
| Start Page: | 1007 |
| End Page: | 1024.e13 |
| Language: | English |
| DOI: | 10.1016/j.ccell.2025.03.007 |
| PUBMED: | 40154481 |
| PROVIDER: | scopus |
| DOI/URL: | |
| Notes: | Article -- Source: Scopus |
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