Search: onr:"swepub:oai:prod.swepub.kib.ki.se:150080643" >
Patient-specific MD...
Patient-specific MDS-RS iPSCs define the mis-spliced transcript repertoire and chromatin landscape of SF3B1-mutant HSPCs
-
Asimomitis, G (author)
-
Deslauriers, AG (author)
-
Kotini, AG (author)
-
show more...
-
Bernard, E (author)
-
Esposito, D (author)
-
Olszewska, M (author)
-
Spyrou, N (author)
-
Ossa, JA (author)
-
- Mortera-Blanco, T (author)
- Karolinska Institutet
-
Koche, R (author)
-
Malcovati, L (author)
-
Ogawa, S (author)
-
Cazzola, M (author)
-
Aaronson, SA (author)
-
Hellstro-Lindberg, E (author)
-
Papaemmanuil, E (author)
-
Nannya, Y (author)
-
Papapetrou, EP (author)
-
show less...
-
(creator_code:org_t)
- 2022-05-16
- 2022
- English.
-
In: Blood advances. - : American Society of Hematology. - 2473-9537 .- 2473-9529. ; 6:10, s. 2992-3005
- Related links:
-
https://ashpublicati...
-
show more...
-
http://kipublication...
-
https://doi.org/10.1...
-
show less...
Abstract
Subject headings
Close
- 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.
Publication and Content Type
- ref (subject category)
- art (subject category)
Find in a library
To the university's database
- By the author/editor
-
Asimomitis, G
-
Deslauriers, AG
-
Kotini, AG
-
Bernard, E
-
Esposito, D
-
Olszewska, M
-
show more...
-
Spyrou, N
-
Ossa, JA
-
Mortera-Blanco, ...
-
Koche, R
-
Malcovati, L
-
Ogawa, S
-
Cazzola, M
-
Aaronson, SA
-
Hellstro-Lindber ...
-
Papaemmanuil, E
-
Nannya, Y
-
Papapetrou, EP
-
show less...
- Articles in the publication
-
Blood advances
- By the university
-
Karolinska Institutet