Impaired hematopoiesis and leukemia development in mice with a conditional knock-in allele of a mutant splicing factor gene U2af1 Journal Article

   

Authors:	Fei, D. L.; Zhen, T.; Durham, B.; Ferrarone, J.; Zhang, T.; Garrett, L.; Yoshimi, A.; Abdel-Wahab, O.; Bradley, R. K.; Liu, P.; Varmus, H.
Article Title:	Impaired hematopoiesis and leukemia development in mice with a conditional knock-in allele of a mutant splicing factor gene U2af1
Abstract:	Mutations affecting the spliceosomal protein U2AF1 are commonly found in myelodysplastic syndromes (MDS) and secondary acute myeloid leukemia (sAML). We have generated mice that carry Credependent knock-in alleles of U2af1(S34F), the murine version of the most common mutant allele of U2AF1 encountered in human cancers. Cre-mediated recombination inmurine hematopoietic lineages caused changes in RNA splicing, as well as multilineage cytopenia, macrocytic anemia, decreased hematopoietic stem and progenitor cells, lowgrade dysplasias, and impaired transplantability, but without lifespan shortening or leukemia development. In an attempt to identify U2af1(S34F)-cooperating changes that promote leukemogenesis, we combined U2af1(S34F) with Runx1 deficiency in mice and further treated the mice with a mutagen, N-ethyl-N-nitrosourea (ENU). Overall, 3 of 16 ENU-treated compound transgenic mice developed AML. However, AML did not arise in mice with other genotypes or without ENU treatment. Sequencing DNA from the three AMLs revealed somatic mutations homologous to those considered to be drivers of human AML, including predicted loss- or gain-of-function mutations in Tet2, Gata2, Idh1, and Ikzf1. However, the engineered U2af1(S34F) missense mutation reverted to WT in two of the three AML cases, implying that U2af1(S34F) is dispensable, or even selected against, once leukemia is established. © 2018 National Academy of Sciences. All rights reserved.
Keywords:	leukemia; myelodysplastic syndromes; splicing factor; u2af1; s34f
Journal Title:	Proceedings of the National Academy of Sciences of the United States of America
Volume:	115
Issue:	44
ISSN:	0027-8424
Publisher:	National Academy of Sciences
Date Published:	2018-10-30
Start Page:	E10437
End Page:	E10446
Language:	English
DOI:	10.1073/pnas.1812669115
PUBMED:	30322915
PROVIDER:	scopus
PMCID:	PMC6217397
DOI/URL:	https://www.scopus.com/inward/record.uri?eid=2-s2.0-85055667094&doi=10.1073%2fpnas.1812669115&partnerID=40&md5=0d6597b4f359fea46614daa290410663
Notes:	Article -- Export Date: 3 December 2018 -- Source: Scopus

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