Concurrent Zrsr2 mutation and Tet2 loss promote myelodysplastic neoplasm in mice

被引:6
作者
Garcia-Ruiz, Cristian [1 ]
Martinez-Valiente, Cristina [1 ]
Cordon, Lourdes [1 ,2 ]
Liquori, Alessandro [1 ,2 ]
Fernandez-Gonzalez, Raul [3 ]
Pericuesta, Eva [3 ]
Sandoval, Juan [4 ]
Cervera, Jose [2 ,5 ,6 ]
Gutierrez-Adan, Alfonso [3 ]
Sanjuan-Pla, Alejandra [1 ]
机构
[1] Inst Invest Sanitaria La Fe IISLAFE, Hematol Res Grp, Avda Fernando Abril Martorell 106, Valencia 46026, Spain
[2] Ctr Invest Biomed Red Canc CIBER ONC, Av Monforte de Lemos,3-5 Pabellon 11 Planta 0, Madrid 28029, Spain
[3] INIA CSIC, Anim Reprod Dept, Ctra La Coruna,Km 5,9, Madrid 28040, Spain
[4] Inst Invest Sanitaria La Fe IISLAFE, Epigen Core Facil, Avda Fernando Abril Martorell, Valencia 46026, Spain
[5] Hosp Univ & Politecn La Fe, Hematol Serv, Avda Fernando Abril Martorell 106, Valencia 46026, Spain
[6] Hosp Univ & Politecn La Fe, Genet Unit, Avda Fernando Abril Martorell 106, Valencia 46026, Spain
关键词
HEMATOPOIETIC STEM-CELLS; PROGENITOR CELLS; EXPRESSION; PATHOGENESIS; DISORDERS; DELETION; MOUSE; LEADS;
D O I
10.1038/s41375-022-01674-2
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
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 Zrsr2(m/m)Tet2(-/-) 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.
引用
收藏
页码:2509 / 2518
页数:10
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