Distinct routes of clonal progression in SF3B1-mutant myelodysplastic syndromes
Myelodysplastic syndromes (MDS) are clonal stem cell disorders driven by heterogeneous genetic alterations leading to variable clinical course. MDS with splicing factor SF3B1 mutations is a distinct subtype with a favorable outcome. However, selected comutations induce poor prognosis and how these genetic lesions cooperate in human hematopoietic stem and progenitor cells (HSPCs) during disease progression is still unclear. Here, we integrated clinical and molecular profiling of patients with SF3B1 mutations with gene editing of primary and induced pluripotent stem cell-derived human HSPCs to show that high-risk comutations impart distinct effects on lineage programs of SF3B1-mutant HSPCs. Secondary RUNX1 or STAG2 mutations were clinically associated with advanced disease and reduced survival. However, RUNX1 and STAG2 mutations induced opposing regulation of myeloid transcriptional programs and differentiation in SF3B1-mutant HSPCs. Moreover, high-risk RUNX1 and STAG2, but not low-risk TET2, mutations expanded distinct SF3B1-mutant HSPC subpopulations. These findings provide evidence that progression from low- to high-risk MDS involves distinct molecular and cellular routes depending on comutation patterns.
Authors
- Laura D. Baquero Galvis (ORCID: https://orcid.org/0009-0008-1478-0964)
- Anna Gallì (ORCID: https://orcid.org/0000-0002-7912-6428)
- J. Philip Creamer (ORCID: https://orcid.org/0000-0002-5147-3866)
- Sara Pozzi (ORCID: https://orcid.org/0000-0002-9121-0876)
- Edie I. Crosse (ORCID: https://orcid.org/0000-0002-0477-7365)
- Sergei Doulatov (ORCID: https://orcid.org/0000-0002-1328-364X)
- Courtnee Clough (ORCID: https://orcid.org/0000-0002-7859-7252)
- Chiara Elena (ORCID: https://orcid.org/0000-0002-0058-7142)
- Robert K. Bradley (ORCID: https://orcid.org/0000-0002-8046-1063)
- Martina Sarchi (ORCID: https://orcid.org/0000-0002-1557-6577)
- Béatrice Ferrari (ORCID: https://orcid.org/0000-0003-3032-608X)
- Luca Malcovati (ORCID: https://orcid.org/0000-0002-1460-1611)
- Cristina Picone (ORCID: https://orcid.org/0000-0002-4609-3965)
- Elisabetta Molteni
- Nelli Aydinyan (ORCID: https://orcid.org/0009-0005-1194-7421)
- Claudia Fiducioso
Institutions
- Cape Town HVTN Immunology Laboratory / Hutchinson Centre Research Institute of South Africa (ZA)
- California Institute for Regenerative Medicine (US)
- University of Washington (US)
- University of Pavia (IT)
- Fred Hutch Cancer Center (US)
- University Hospital Foundation (CA)
- Intermolecular (United States) (US)
- Policlinico San Matteo Fondazione (IT)
- Istituti di Ricovero e Cura a Carattere Scientifico (IT)
Publication Details
- Journal
- Blood Advances
- Published
- 2025-04-06
- DOI
- https://doi.org/10.1182/bloodadvances.2024014965
- Citations
- 4
- Primary Topic
- Acute Myeloid Leukemia Research
- Type
- article
- Field-Weighted Citation Impact
- 7.08
Funders
- Damon Runyon Cancer Research Foundation
- Leukemia and Lymphoma Society
- University of Washington
- Edward P. Evans Foundation
- Cancer Research UK
- Università degli Studi di Pavia
- Associazione Italiana per la Ricerca sul Cancro
- National Institutes of Health
- National Heart, Lung, and Blood Institute
- National Cancer Institute
- National Institute of Diabetes and Digestive and Kidney Diseases