U2af1 is a haplo-essential gene required for hematopoietic cancer cell survival in mice

• Published in: The Journal of clinical investigation 2021-11, Vol.131 (21), p.1-15
• Main Authors: Wadugu, Brian A, Nonavinkere Srivatsan, Sridhar, Heard, Amanda, Alberti, Michael O, Ndonwi, Matthew, Liu, Jie, Grieb, Sarah, Bradley, Joseph, Shao, Jin, Ahmed, Tanzir, Shirai, Cara L, Khanna, Ajay, Fei, Dennis L, Miller, Christopher A, Graubert, Timothy A, Walter, Matthew J
• Format: Article
• Language: English
• Subjects: Alleles; Amino acids; Animals; Apoptosis; Biomedical research; Blood cancer; Bone marrow; Cancer; Cell death; Cell survival; Development and progression; Gene mutations; Genes; Genetic aspects; Health aspects; Hematologic Neoplasms - genetics; Hematologic Neoplasms - metabolism; Hematopoietic stem cells; Heterozygote; Leukemia; Leukemia - genetics; Leukemia - metabolism; Liver; Mice; Mice, Knockout; Mutants; Mutation; Myelodysplastic syndrome; Myelodysplastic syndromes; Neoplasm Proteins - biosynthesis; Neoplasm Proteins - genetics; Neoplasms, Experimental - genetics; Neoplasms, Experimental - metabolism; Splicing Factor U2AF - biosynthesis; Splicing Factor U2AF - genetics; Stem cells; Tumors
• ISSN: 1558-8238; 0021-9738; 1558-8238
• DOI: 10.1172/JCI141401

Somatic mutations in the spliceosome gene U2AF1 are common in patients with myelodysplastic syndromes. U2AF1 mutations that code for the most common amino acid substitutions are always heterozygous, and the retained WT allele is expressed, suggesting that mutant hematopoietic cells may require the residual WT allele to be viable. We show that hematopoiesis and RNA splicing in U2af1 heterozygous knockout mice were similar to those in control mice, but that deletion of the WT allele in U2AF1(S34F) heterozygous mutant-expressing hematopoietic cells (i.e., hemizygous mutant) was lethal. These results confirm that U2AF1 mutant hematopoietic cells are dependent on the expression of WT U2AF1 for survival in vivo and that U2AF1 is a haplo-essential cancer gene. Mutant U2AF1(S34F)-expressing cells were also more sensitive to reduced expression of WT U2AF1 than nonmutant cells. Furthermore, mice transplanted with leukemia cells expressing mutant U2AF1 had significantly reduced tumor burden and improved survival after the WT U2af1 allele was deleted compared with when it was not deleted. These results suggest that selectively targeting the WT U2AF1 allele in heterozygous mutant cells could induce cancer cell death and be a therapeutic strategy for patients harboring U2AF1 mutations.