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

Fecha de publicación: 01/07/2021 Fecha Ahead of Print: 28/06/2021

Autores de IIS La Fe

Participantes ajenos a IIS La Fe

Fernández-González R
Gómez-Redondo I
Gutiérrez-Adán A

Grupos

Hematología y Hemoterapia

Investigador Principal

Javier De La Rubia Comos

Abstract

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 (U2af1(mut/+)), studied the U2af1(mut/+) hematopoietic system, and did not observe any gross differences in both young (12-13 weeks) and old (23 months) U2af1(mut/+) 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 U2af1(mut/+) in conjunction with Tet2-deficiency. Novel double mutant U2af1(mut/+) Tet2(-/-) mice showed increased monogranulocytic precursors. Hematopoietic stem/progenitor cells were also enhanced and presented functional and transcriptomic alterations. Nonetheless, U2af1(mut/+) 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.

Datos de la publicación

ISSN/ISSNe:: 1661-6596, 1661-6596
Tipo:: Article
Páginas:: -
DOI:: 10.3390/ijms22136963
Factor de Impacto:: 1,176 SCImago ℠
Cuartil:: Q1 SCImago ℠

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Filiaciones

Martínez-Valiente C:: Instituto de Investigación. Inst Invest Sanitaria La Fe, Hematol Res Grp, Avda Fernando Abril Martorell 106, Valencia 46026, Spain
Garcia-Ruiz C:: Instituto de Investigación. Inst Invest Sanitaria La Fe, Hematol Res Grp, Avda Fernando Abril Martorell 106, Valencia 46026, Spain
Rosón B:: Instituto de Investigación. Inst Invest Sanitaria La Fe, Hematol Res Grp, Avda Fernando Abril Martorell 106, Valencia 46026, Spain
Liquori A:: Instituto de Investigación. Inst Invest Sanitaria La Fe, Hematol Res Grp, Avda Fernando Abril Martorell 106, Valencia 46026, Spain
González-Romero E:: Instituto de Investigación. Inst Invest Sanitaria La Fe, Hematol Res Grp, Avda Fernando Abril Martorell 106, Valencia 46026, Spain
Fernández-González R:: INIA, Dept Anim Reprod, Ctra Coruna Km 7-5, Madrid 28040, Spain
Gómez-Redondo I:: INIA, Dept Anim Reprod, Ctra Coruna Km 7-5, Madrid 28040, Spain
Cervera J:: Hosp Univ & Politecn La Fe, Hematol Serv, Avda Fernando Abril Martorell 106, Valencia 46026, Spain

Ctr Invest Biomed Red Canc CIBER ONC, Av Monforte de Lemos 3-5,Pabellon 11, Madrid 28029, Spain

Hosp Univ & Politecn La Fe, Genet Unit, Avda Fernando Abril Martorell 106, Valencia 46026, Spain
Gutiérrez-Adán A:: INIA, Dept Anim Reprod, Ctra Coruna Km 7-5, Madrid 28040, Spain
Sanjuan-Pla A:: Instituto de Investigación. Inst Invest Sanitaria La Fe, Hematol Res Grp, Avda Fernando Abril Martorell 106, Valencia 46026, Spain