Integrative RNA-omics Discovers GNAS Alternative Splicing as a Phenotypic Driver of Splicing Factor-Mutant Neoplasms.

Autor:	Wheeler EC; Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, California.; Stem Cell Program, University of California, San Diego, La Jolla, California.; Institute for Genomic Medicine, University of California, San Diego, La Jolla, California., Vora S; Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York.; Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York.; Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai, New York, New York.; Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York., Mayer D; Department of Pharmacology, University of California San Diego School of Medicine, La Jolla, California., Kotini AG; Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York.; Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York.; Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai, New York, New York.; Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York., Olszewska M; Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York.; Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York.; Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai, New York, New York.; Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York., Park SS; Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, California., Guccione E; Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York.; Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York.; Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai, New York, New York., Teruya-Feldstein J; Department of Pathology, Molecular and Cell-Based Medicine, Icahn School of Medicine at Mount Sinai, New York, New York., Silverman L; Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York.; Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York., Sunahara RK; Department of Pharmacology, University of California San Diego School of Medicine, La Jolla, California., Yeo GW; Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, California.; Stem Cell Program, University of California, San Diego, La Jolla, California.; Institute for Genomic Medicine, University of California, San Diego, La Jolla, California., Papapetrou EP; Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York.; Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York.; Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai, New York, New York.; Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York.
Jazyk:	angličtina
Zdroj:	Cancer discovery [Cancer Discov] 2022 Mar 01; Vol. 12 (3), pp. 836-855.
DOI:	10.1158/2159-8290.CD-21-0508
Abstrakt:	Mutations in splicing factors (SF) are the predominant class of mutations in myelodysplastic syndrome (MDS), but convergent downstream disease drivers remain elusive. To identify common direct targets of missplicing by mutant U2AF1 and SRSF2, we performed RNA sequencing and enhanced version of the cross-linking and immunoprecipitation assay in human hematopoietic stem/progenitor cells derived from isogenic induced pluripotent stem cell (iPSC) models. Integrative analyses of alternative splicing and differential binding converged on a long isoform of GNAS (GNAS-L), promoted by both mutant factors. MDS population genetics, functional and biochemical analyses support that GNAS-L is a driver of MDS and encodes a hyperactive long form of the stimulatory G protein alpha subunit, Gαs-L, that activates ERK/MAPK signaling. SF-mutant MDS cells have activated ERK signaling and consequently are sensitive to MEK inhibitors. Our findings highlight an unexpected and unifying mechanism by which SRSF2 and U2AF1 mutations drive oncogenesis with potential therapeutic implications for MDS and other SF-mutant neoplasms. Significance: SF mutations are disease-defining in MDS, but their critical effectors remain unknown. We discover the first direct target of convergent missplicing by mutant U2AF1 and SRSF2, a long GNAS isoform, which activates G protein and ERK/MAPK signaling, thereby driving MDS and rendering mutant cells sensitive to MEK inhibition. This article is highlighted in the In This Issue feature, p. 587. (©2021 American Association for Cancer Research.)
Databáze:	MEDLINE
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