Knockdown of spliceosome U2AF1 significantly inhibits the development of human erythroid cells

Zhang, Jieying; Zhao, Hengyu; Wu, Kunlu; Peng, Yuanliang; Han, Xu; Zhang, Huan; Liang, Long; Chen, Huiyong; Hu, Jingping; Qu, Xiaoli; Zhang, Shijie; Chen, Lixiang; Liu, Jing

doi:10.1111/jcmm.14370

Cited by 7 publications

(6 citation statements)

References 50 publications

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“…Genes involved in pre-mRNA splicing, response to unfolded protein, and intrinsic apoptotic signaling pathway in response to ER stress were significantly upregulated in homozygous U2af1 KO cells but not in heterozygous U2af1 KO cells compared to control cells (Supplemental Table 3). Upregulation of genes involved in apoptosis was consistent with the previous report of U2AF1 knockdown in human erythroblasts (35) and our observed increase in apoptotic (annexin V + , viability-marker -) KL cells in the Vav1-Cre/U2af1 flox/flox mouse fetal liver cells compared to Vav1-Cre/U2af1 wt/flox , U2af1 flox/flox and Vav1-Cre cells (Supplemental Figure 2D).…”

Section: U2af1 Deletion Dysregulates the Expression Of Genes Involved In Splicing Unfolded Protein Response And Apoptosissupporting

confidence: 92%

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

Wadugu¹,

Srivatsan²,

Heard³

et al. 2021

Journal of Clinical Investigation

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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 wild-type allele is expressed, suggesting that mutant hematopoietic cells may require the residual wild-type allele to be viable. We show that hematopoiesis and RNA splicing in U2af1 heterozygous knock-out mice was similar to control mice, but that deletion of the wild-type 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 wild-type 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 wild-type U2AF1 than non-mutant cells.Furthermore, mice transplanted with leukemia cells expressing mutant U2AF1 had significantly reduced tumor burden and improved survival after the wild-type U2af1 allele was deleted compared to when it was not deleted. These results suggest that selectively targeting the wildtype U2AF1 allele in heterozygous mutant cells could induce cancer cell death and be a therapeutic strategy for patients harboring U2AF1 mutations.

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Section: U2af1 Deletion Dysregulates the Expression Of Genes Involved In Splicing Unfolded Protein Response And Apoptosissupporting

confidence: 92%

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

Wadugu¹,

Srivatsan²,

Heard³

et al. 2021

Journal of Clinical Investigation

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“…However, there was no significant difference between the two groups, which was probably related to the small sample size. Zhang et al 22 have shown that U2AF1 mutation can affect the expression of p53 signaling pathway and MAPK signaling pathway proteins by down-regulating the transcription of related genes. Therefore, we speculate that Q157P mutation of U2AF1 may lead to genetic instability and increase the incidence of some specific pathogenic genes by down-regulating the transcription of related genes, thus affecting the progress and prognosis of the disease.…”

Section: Discussionmentioning

confidence: 99%

Differential U2AF1 mutation sites, burden and co-mutation genes can predict prognosis in patients with myelodysplastic syndrome

Wang

Guo

Dong

et al. 2020

Sci Rep

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To investigate the U2AF1 gene mutation site, mutation load and co-mutations genes in patients with myelodysplastic syndrome (MDS) and their effects on prognosis. Gene mutation detection by next-generation sequence and related clinical data of 234 MDS patients were retrospectively collected and analyzed for the relationship between the clinical characteristics, treatment efficacy and prognosis of U2AF1 gene mutation. Among the 234 MDS patients, the U2AF1 gene mutation rate was 21.7% (51 cases), and the median variant allele frequency was 39.5%. Compared with the wild type, the U2AF1 mutant had a higher incidence of chromosome 8 aberration, and was positively correlated with the occurrence of ASXL1, RUNX1, SETBP1 gene mutation, negatively correlated with SF3B1, NPM1 genes mutation (p < 0.05). The most common mutation site of U2AF1 was S34F (32 cases), while U2AF1 Q157P site mutations had a higher incidence of chromosome 7 abnormalities (p = 0.003). The U2AF1 gene mutation more frequently coincided with signal pathway related gene mutations (p = 0.043) with a trend of shortened overall survival. Among patients with U2AF1 gene mutations, those with ASXL1 mutations were prone to develop into acute myeloid leukemia, those with RUNX1 mutations had an increased risk of relapse, and those with TET2 mutations had higher 1-year survival rate. Compared with the patient group of lower mutation load (VAF ≤ 40%), the group with higher mutation load of U2AF1 (VAF > 40%) had a significantly lower 1-year survival rate (46.1% and 80.5%, p = 0.027). The criteria of U2AF1 VAF > 40% is an independent indicator for poor prognosis of MDS patients. VAF > 40% of U2AF1 is an independent factor of short OS in MDS patients. MDS patients with a mutation in the Q157P site of U2AF1 and a higher U2AF1 mutation load suggests poor prognosis, and co-mutated genes in U2AF1 can affect disease progression and prognosis.

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“… 26 More importantly, the link with U2AF1 and erythropoiesis was further explored in a series of assays by Zhang et al, who demonstrated that U2AF1 plays a critical role in erythropoiesis through regulation of alternative splicing, which was further highlighted by the fact that it was significantly expressed in the progenitor burst-forming-unit and colony-forming-unit stages of erythroid maturation. 27 …”

Section: Discussionmentioning

confidence: 99%

U2AF1 and EZH2 mutations are associated with nonimmune hemolytic anemia in myelodysplastic syndromes

et al. 2023

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Hemolysis is a well-recognized but poorly characterized phenomenon in a subset of patients with myelodysplastic syndromes (MDS). Its pathobiological basis seems to underpin a nonimmune etiology whose clinical significance has not been adequately characterized. Hemolysis in MDS is often attributed to either ineffective intramedullary erythropoiesis or acquired hemoglobinopathies and red blood cell (RBC) membrane defects. These heterogenous processes have not been associated with specific genetic subsets of disease. We aimed to describe the prevalence of hemolysis among MDS patients, their baseline characteristics, molecular features and resulting impact on outcomes. We considered baseline serum haptoglobin <10 mg/dl a surrogate marker for intravascular hemolysis. Among 519 patients, 10% had hemolysis. The baseline characteristics were similar among both groups. Only 13% of patients with hemolysis were Coombs-positive suggesting that hemolysis in MDS is largely not immune-mediated. Inferior survival trends were observed among lower risk MDS patients with hemolysis. Decreased response rates to erythropoiesis-stimulating agents and higher responses to hypomethylating agents (HMA) were also observed in the hemolysis group. U2AF1 and EZH2 hotspot mutations were more prevalent among those undergoing hemolysis (p<0.05). U2AF1 mutations were observed in 30% of patients with hemolysis and occurred almost exclusively at the S34 hotspot. Somatic mutations encoding splicing factors may affect erythrocyte membrane components, biochemical properties, and RBC metabolic function, which underpin the development of atypical clones from erythroid precursors in MDS presenting with hemolysis. Future studies will explore the contribution of altered splicing to the development of acquired hemoglobinopathies.

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Knockdown of spliceosome U2AF1 significantly inhibits the development of human erythroid cells

Cited by 7 publications

References 50 publications

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

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

Differential U2AF1 mutation sites, burden and co-mutation genes can predict prognosis in patients with myelodysplastic syndrome

U2AF1 and EZH2 mutations are associated with nonimmune hemolytic anemia in myelodysplastic syndromes

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