Erythroid differentiation enhances RNA mis-splicing in SF3B1-mutant myelodysplastic syndromes with ring sideroblasts

Journal article

Myelodysplastic syndromes with ring sideroblasts (MDS-RS) commonly develop from hematopoietic stem cells (HSC) bearing mutations in the splicing factor SF3B1 (SF3B1^mt). Direct studies into MDS-RS pathobiology have been limited by a lack of model systems that fully recapitulate erythroid biology and RS development and the inability to isolate viable human RS. Here, we combined successful direct RS isolation from patient samples, high-throughput multiomics analysis of cells encompassing the SF3B1^mt stem-erythroid continuum, and functional assays to investigate the impact of SF3B1^mt on erythropoiesis and RS accumulation. The isolated RS differentiated, egressed into the blood, escaped traditional nonsense-mediated decay (NMD) mechanisms, and leveraged stress-survival pathways that hinder wild-type hematopoiesis through pathogenic GDF15 overexpression. Importantly, RS constituted a contaminant of magnetically enriched CD34⁺ cells, skewing bulk transcriptomic data. Mis-splicing in SF3B1^mt cells was intensified by erythroid differentiation through accelerated RNA splicing and decreased NMD activity, and SF3B1^mt led to truncations in several MDS-implicated genes. Finally, RNA mis-splicing induced an uncoupling of RNA and protein expression, leading to critical abnormalities in proapoptotic p53 pathway genes. Overall, this characterization of erythropoiesis in SF3B1^mt RS provides a resource for studying MDS-RS and uncovers insights into the unexpectedly active biology of the “dead-end” RS.

Significance: Ring sideroblast isolation combined with state-of-the-art multiomics identifies survival mechanisms underlying SF3B1-mutant erythropoiesis and establishes an active role for erythroid differentiation and ring sideroblasts themselves in SF3B1-mutant myelodysplastic syndrome pathogenesis.

Authors: Moura, PL; Mortera Blanco, T; Hofman, IJ; Todisco, G; Kretzschmar, WW

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: American Association for Cancer Research
• Journal: Cancer Research
• Volume: 84
• Issue: 2
• Pages: 211–225
• Place of publication: United States
• Publication date: 2023-11-03
• Acceptance date: 2023-10-31
• DOI: 10.1158/0008-5472.CAN-23-3038
• EISSN: 1538-7445
• ISSN: 0008-5472
• Pmid: 37921711
• Language: English
• Keywords: nonembryonic stem cell research; placenta stem cell research; genetics; biotechnology; blood; umbilical cord blood stem cell research; stem cell research; hematology