Journal Article

Aberrant Alternative Splicing in U2af1/Tet2 Double Mutant Mice Contributes to Major Hematological Phenotypes

Liquori, Alessandro, González-Romero, Elisa, Gómez-Redondo, Isabel, Sanjuan-Pla, Alejandra, Garcia-Ruiz, Cristian, Fernández-González, Raúl, Gutiérrez-Adán, Alfonso, Cervera, José, Rosón, Beatriz, Martínez-Valiente, Cristina

2021

Overview

Mutations in splicing factors are recurrent somatic alterations identified in myelodysplastic syndromes (MDS) and they frequently coincide with mutations in epigenetic factors. About 25% of patients present concurrent mutations in such pathways, suggesting a cooperative role in the pathogenesis of MDS. We focused on the splicing factor U2AF1 involved in the recognition of the 3′ splice site during pre-mRNA splicing. Using a CRISPR/Cas9 system, we created heterozygous mice with a carboxy-terminal truncated U2af1 allele (U2af1mut/+), studied the U2af1mut/+ hematopoietic system, and did not observe any gross differences in both young (12–13 weeks) and old (23 months) U2af1mut/+ mice, except for a reduction in size of approximately 20%. However, hematopoietic stem/progenitor cells lacked reconstitution capacity in transplantation assays and displayed an aberrant RNA splicing by RNA sequencing. We also evaluated U2af1mut/+ in conjunction with Tet2-deficiency. Novel double mutant U2af1mut/+Tet2−/− mice showed increased monogranulocytic precursors. Hematopoietic stem/progenitor cells were also enhanced and presented functional and transcriptomic alterations. Nonetheless, U2af1mut/+Tet2−/− mice did not succumb to MDS disease over a 6-month observation period. Collectively, our data suggest that cooperation between mutant U2af1 and Tet2 loss is not sufficient for MDS initiation in mice.

• Publisher: MDPI AG,MDPI
• Subject: Alternative Splicing - genetics / Alternative Splicing - physiology / Animals / Bone marrow / Clustered Regularly Interspaced Short Palindromic Repeats - genetics / Clustered Regularly Interspaced Short Palindromic Repeats - physiology / CRISPR / Dioxygenases / DNA-Binding Proteins - genetics / DNA-Binding Proteins - metabolism / Epigenetics / Flow cytometry / Hematology / Leukemia / Medical prognosis / Mice / Mutation / Myelodysplastic syndromes / Myelodysplastic Syndromes - genetics / Myelodysplastic Syndromes - metabolism / Pathogenesis / Proteins / Proto-Oncogene Proteins - genetics / Proto-Oncogene Proteins - metabolism / RNA Splicing Factors - genetics / RNA Splicing Factors - metabolism / Rodents / Splicing Factor U2AF - genetics / Splicing Factor U2AF - metabolism / Stem cells / Tumors