Concurrent Zrsr2 mutation and Tet2 loss promote myelodysplastic neoplasm in mice

Autor: Cristian Garcia-Ruiz, Cristina Martínez-Valiente, Lourdes Cordón, Alessandro Liquori, Raúl Fernández-González, Eva Pericuesta, Juan Sandoval, José Cervera, Alfonso Gutiérrez-Adán, Alejandra Sanjuan-Pla
Přispěvatelé: Agencia Estatal de Investigación (España), Ministerio de Economía, Industria y Competitividad (España), Generalitat Valenciana, Ministerio de Ciencia e Innovación (España), Garcia-Ruiz, Cristian, Martínez-Valiente, Cristina, Cordón, Lourdes, Liquori, Alessandro, Fernández-González, Raúl, Pericuesta, Eva, Sandoval, Juan, Gutiérrez-Adán, Alfonso, Sanjuan-Pla, Alejandra
Jazyk: angličtina
Rok vydání: 2022
Předmět:
Zdroj: Leukemia
r-IIS La Fe. Repositorio Institucional de Producción Científica del Instituto de Investigación Sanitaria La Fe
instname
ISSN: 0887-6924
Popis: 10 Pág.
RNA splicing and epigenetic gene mutations are the most frequent genetic lesions found in patients with myelodysplastic neoplasm (MDS). About 25% of patients present concomitant mutations in such pathways, suggesting a cooperative role in MDS pathogenesis. Importantly, mutations in the splicing factor ZRSR2 frequently associate with alterations in the epigenetic regulator TET2. However, the impact of these concurrent mutations in hematopoiesis and MDS remains unclear. Using CRISPR/Cas9 genetically engineered mice, we demonstrate that Zrsr2m/mTet2-/- promote MDS with reduced penetrance. Animals presented peripheral blood cytopenia, splenomegaly, extramedullary hematopoiesis, and multi-lineage dysplasia, signs consistent with MDS. We identified a myelo-erythroid differentiation block accompanied by an expansion of LT-HSC and MPP2 progenitors. Transplanted animals presented a similar phenotype, thus indicating that alterations were cell-autonomous. Whole-transcriptome analysis in HSPC revealed key alterations in ribosome, inflammation, and migration/motility processes. Moreover, we found the MAPK pathway as the most affected target by mRNA aberrant splicing. Collectively, this study shows that concomitant Zrsr2 mutation and Tet2 loss are sufficient to initiate MDS in mice. Understanding this mechanistic interplay will be crucial for the identification of novel therapeutic targets in the spliceosome/epigenetic MDS subgroup.
This investigation was supported by the grant SAF2017-82171-R to ASP from the Spanish Ministry of Economy, Industry, and Competitiveness. CGR is founded by JAP Valencia AECC predoctoral fellowships. CMV is sponsored by a predoctoral fellowship from Generalitat Valenciana (ACIF/2018/255). AL is funded by Generalitat Valenciana (APOSTD/2021/212). AGA was funded by grant RTI2018-093548-B-I00 from the Spanish Ministry of Science and Innovation. ASP is supported by the Ramón y Cajal Program (RYC2015-17534)
Databáze: OpenAIRE
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