@article{e5df46789a5e4b6ab9b11345157244dd,
title = "Mutant U2AF1-induced alternative splicing of H2afy (macroH2A1) regulates B-lymphopoiesis in mice",
abstract = "Somatic mutations in spliceosome genes are found in ∼50% of patients with myelodysplastic syndromes (MDS), a myeloid malignancy associated with low blood counts. Expression of the mutant splicing factor U2AF1(S34F) alters hematopoiesis and mRNA splicing in mice. Our understanding of the functionally relevant alternatively spliced target genes that cause hematopoietic phenotypes in vivo remains incomplete. Here, we demonstrate that reduced expression of H2afy1.1, an alternatively spliced isoform of the histone H2A variant gene H2afy, is responsible for reduced B cells in U2AF1(S34F) mice. Deletion of H2afy or expression of U2AF1(S34F) reduces expression of Ebf1 (early B cell factor 1), a key transcription factor for B cell development, and mechanistically, H2AFY is enriched at the EBF1 promoter. Induced expression of H2AFY1.1 in U2AF1(S34F) cells rescues reduced EBF1 expression and B cells numbers in vivo. Collectively, our data implicate alternative splicing of H2AFY as a contributor to lymphopenia induced by U2AF1(S34F) in mice and MDS.",
keywords = "B-lymphopoiesis, EBF1, H2AFY, U2AF1, U2AF1(S34F), alternative splicing, hematopoiesis, macroH2A1, myelodysplastic syndromes, spliceosome gene mutations",
author = "Kim, {Sanghyun P.} and Srivatsan, {Sridhar N.} and Monique Chavez and Shirai, {Cara L.} and White, {Brian S.} and Tanzir Ahmed and Michael Alberti and Jin Shao and Ryan Nunley and White, {Lynn S.} and Jeff Bednarski and Pehrson, {John R.} and Walter, {Matthew J.}",
note = "Funding Information: The authors thank Drs. Timothy Ley and Dan Link for helpful scientific discussions and Drs. Li Ding and Reyka Jayasinghe for discussion of H2AFY expression in various datasets. The authors thank Drs. Matthew Ndonwi, Shawn Jin, Tianjiao Wang, Sara Arenas, and Christian Rosa-Birriel for technical assistance. Dr. Kim Trinkaus at the Siteman Cancer Center Biostatistics Shared Resource provided helpful advice regarding the limiting dilution assay. This work was supported by the Siteman Cancer Center (Cancer Biology Pathway pre-doctoral fellowship T32 CA113275 and P30 CA091842 to S.P.K.) and grants from the Edward P. Evans Foundation (to M.J.W.), the Taub Foundation (to M.J.W.), the Lottie Caroline Hardy Trust (to M.J.W.), an NIH/NCI grant (K12 CA167540; to B.S.W. M.O.A. and C.L.S.), and a Clinical and Translational Award from the NIH National Center for Advancing Translational Sciences (UL1 TR000448 to B.S.W.). Support for procurement of human samples and research was provided by the Genomics of AML Program Project of the NCI (P01 CA101937) and the Specialized Program of Research Excellence in AML (P50 CA171963). Core services were provided by the Siteman Cancer Center Tissue Procurement Core, the Flow Cytometry Core, the Genome Technology Access Center, and the Division of Comparative Medicine at Washington University School of Medicine. The Siteman Cancer Center is supported in part by NCI Cancer Center Support grant P30 CA091842. The study was designed by S.P.K. and M.J.W. Mouse characterization was done by S.P.K. and M.C. and data analysis was by S.P.K. M.J.W. M.O.A. L.S.W. J.B. and J.R.P. Nanostring design and data generation was performed by B.S.W. C.L.S. S.N.S. and M.J.W. RNA-seq was done by S.P.K. Bioinformatic analysis of data was performed by S.P.K. S.N.S. B.S.W. and M.J.W. S.P.K. J.S. R.N. and T.A. analyzed clinical samples. S.P.K. and M.J.W. wrote the paper. R.N. is a paid consult for Biocomposites, DePuy, Medical Compression Systems, Inc. Mirus, Cardinal Health, Halyard, Medtronic, and Smith & Nephew. R.N. receives research support from Biomet, Medical Compressions Systems, Stryker, DePuy, and Smith & Nephew. The other authors declare no competing interests. Funding Information: The authors thank Drs. Timothy Ley and Dan Link for helpful scientific discussions and Drs. Li Ding and Reyka Jayasinghe for discussion of H2AFY expression in various datasets. The authors thank Drs. Matthew Ndonwi, Shawn Jin, Tianjiao Wang, Sara Arenas, and Christian Rosa-Birriel for technical assistance. Dr. Kim Trinkaus at the Siteman Cancer Center Biostatistics Shared Resource provided helpful advice regarding the limiting dilution assay. This work was supported by the Siteman Cancer Center (Cancer Biology Pathway pre-doctoral fellowship T32 CA113275 and P30 CA091842 to S.P.K.) and grants from the Edward P. Evans Foundation (to M.J.W.), the Taub Foundation (to M.J.W.), the Lottie Caroline Hardy Trust (to M.J.W.), an NIH/NCI grant ( K12 CA167540 ; to B.S.W., M.O.A., and C.L.S.), and a Clinical and Translational Award from the NIH National Center for Advancing Translational Sciences ( UL1 TR000448 to B.S.W.). Support for procurement of human samples and research was provided by the Genomics of AML Program Project of the NCI ( P01 CA101937 ) and the Specialized Program of Research Excellence in AML ( P50 CA171963 ). Core services were provided by the Siteman Cancer Center Tissue Procurement Core, the Flow Cytometry Core, the Genome Technology Access Center, and the Division of Comparative Medicine at Washington University School of Medicine. The Siteman Cancer Center is supported in part by NCI Cancer Center Support grant P30 CA091842 . Publisher Copyright: {\textcopyright} 2021 The Author(s)",
year = "2021",
month = aug,
day = "31",
doi = "10.1016/j.celrep.2021.109626",
language = "English",
volume = "36",
journal = "Cell Reports",
issn = "2211-1247",
number = "9",
}