Patient-specific MDS-RS iPSCs define the mis-spliced transcript repertoire and chromatin landscape of SF3B1-mutant HSPCs Journal Article

   

Authors:	Asimomitis, G.; Deslauriers, A. G.; Kotini, A. G.; Bernard, E.; Esposito, D.; Olszewska, M.; Spyrou, N.; Ossa, J. A.; Mortera-Blanco, T.; Koche, R.; Nannya, Y.; Malcovati, L.; Ogawa, S.; Cazzola, M.; Aaronson, S. A.; Hellström-Lindberg, E.; Papaemmanuil, E.; Papapetrou, E. P.
Article Title:	Patient-specific MDS-RS iPSCs define the mis-spliced transcript repertoire and chromatin landscape of SF3B1-mutant HSPCs
Abstract:	SF3B1(K700E) 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 SF3B1(K700E)- and SF3B1(WT)-induced pluripotent stem cell (iPSC) lines from patients with MDS with ring sideroblasts (MDS-RS) harboring isolated SF3B1(K700E) 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 SF3B1(K700E) 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 SF3B1(K700E) HSPCs and nominates novel mis-spliced genes and transcriptional programs with putative roles in MDS-RS disease biology.
Keywords:	leukemia; myelodysplastic syndromes; mutations; cells; pathway; clonal evolution; splicing events; charts
Journal Title:	Blood Advances
Volume:	6
Issue:	10
ISSN:	2473-9529
Publisher:	American Society of Hematology
Date Published:	2022-05-24
Start Page:	2992
End Page:	3005
Language:	English
ACCESSION:	WOS:000806767500006
DOI:	10.1182/bloodadvances.2021006325
PROVIDER:	wos
PMCID:	PMC9131920
PUBMED:	35042235
Notes:	Article -- Source: Wos

https://synapse.mskcc.org/synapse/works/has_related_data_chk/196531