Patient-specific MDS-RS iPSCs define the mis-spliced transcript repertoire and chromatin landscape of SF3B1-mutant HSPCs
| العنوان: | Patient-specific MDS-RS iPSCs define the mis-spliced transcript repertoire and chromatin landscape of SF3B1-mutant HSPCs |
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| المؤلفون: | Georgios Asimomitis, André G. Deslauriers, Andriana G. Kotini, Elsa Bernard, Davide Esposito, Malgorzata Olszewska, Nikolaos Spyrou, Juan Arango Ossa, Teresa Mortera-Blanco, Richard Koche, Yasuhito Nannya, Luca Malcovati, Seishi Ogawa, Mario Cazzola, Stuart A. Aaronson, Eva Hellström-Lindberg, Elli Papaemmanuil, Eirini P. Papapetrou |
| المصدر: | Blood Advances. 6:2992-3005 |
| بيانات النشر: | American Society of Hematology, 2022. |
| سنة النشر: | 2022 |
| مصطلحات موضوعية: | Myelodysplastic Syndromes, Induced Pluripotent Stem Cells, Mutation, Humans, RNA Splicing Factors, Hematology, Phosphoproteins, Chromatin, Transcription Factors |
| الوصف: | SF3B1K700E is the most frequent mutation in myelodysplastic syndrome (MDS), but the mechanisms by which it drives MDS pathogenesis remain unclear. We derived a panel of 18 genetically matched SF3B1K700E- and SF3B1WT-induced pluripotent stem cell (iPSC) lines from patients with MDS with ring sideroblasts (MDS-RS) harboring isolated SF3B1K700E mutations and performed RNA and ATAC sequencing in purified CD34+/CD45+ hematopoietic stem/progenitor cells (HSPCs) derived from them. We developed a novel computational framework integrating splicing with transcript usage and gene expression analyses and derived a SF3B1K700E splicing signature consisting of 59 splicing events linked to 34 genes, which associates with the SF3B1 mutational status of primary MDS patient cells. The chromatin landscape of SF3B1K700E HSPCs showed increased priming toward the megakaryocyte- erythroid lineage. Transcription factor motifs enriched in chromatin regions more accessible in SF3B1K700E cells included, unexpectedly, motifs of the TEA domain (TEAD) transcription factor family. TEAD expression and transcriptional activity were upregulated in SF3B1-mutant iPSC-HSPCs, in support of a Hippo pathway-independent role of TEAD as a potential novel transcriptional regulator of SF3B1K700E cells. This study provides a comprehensive characterization of the transcriptional and chromatin landscape of SF3B1K700E HSPCs and nominates novel mis-spliced genes and transcriptional programs with putative roles in MDS-RS disease biology. |
| تدمد: | 2473-9537 2473-9529 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::31cacbda698ea36101459c3fc5472ad7 https://doi.org/10.1182/bloodadvances.2021006325 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....31cacbda698ea36101459c3fc5472ad7 |
| قاعدة البيانات: | OpenAIRE |
Full Text via ClinicalKey | تدمد: | 24739537 24739529 |
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