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Proc Natl Acad Sci U S A. 2018 Oct 30;115(44):E10437-E10446. doi: 10.1073/pnas.1812669115. Epub 2018 Oct 15.

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

Author information

1
Department of Medicine, Weill Cornell Medicine, New York, NY 10065; dennisfei@hotmail.com pliu@mail.nih.gov varmus@med.cornell.edu.
2
Meyer Cancer Center, Weill Cornell Medicine, New York, NY 10065.
3
Cancer Biology Section, Cancer Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892.
4
Oncogenesis and Development Section, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892.
5
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065.
6
Department of Medicine, Weill Cornell Medicine, New York, NY 10065.
7
Genomics Resources Core Facility, Weill Cornell Medicine, New York, NY 10065.
8
Department of Microbiology and Immunology, Weill Cornell Medicine, New York, NY 10065.
9
Embryonic Stem Cell and Transgenic Mouse Core, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892.
10
Leukemia Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065.
11
Computational Biology Program, Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109.
12
Basic Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109.
13
Oncogenesis and Development Section, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892; dennisfei@hotmail.com pliu@mail.nih.gov varmus@med.cornell.edu.
14
New York Genome Center, New York, NY 10013.

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 Cre-dependent knock-in alleles of U2af1(S34F), the murine version of the most common mutant allele of U2AF1 encountered in human cancers. Cre-mediated recombination in murine hematopoietic lineages caused changes in RNA splicing, as well as multilineage cytopenia, macrocytic anemia, decreased hematopoietic stem and progenitor cells, low-grade 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.

KEYWORDS:

S34F; U2AF1; leukemia; myelodysplastic syndromes; splicing factor

PMID:
30322915
PMCID:
PMC6217397
DOI:
10.1073/pnas.1812669115
[Indexed for MEDLINE]
Free PMC Article

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