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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5669537 | PMC |
| http://dx.doi.org/10.1172/JCI96202 | DOI Listing |
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Aberrant splicing of CHEK1 is a driver of megakaryocytic dysplasia in U2AF1 mutant myelodysplastic neoplasms.
Leukemia
September 2025
State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China.
U2AF1 mutations are common in patients with myelodysplastic neoplasms (MDS), suggesting that aberrant splicing of pre-mRNAs driven by mutant U2AF1 could play a critical role in MDS pathogenesis. Previous studies have demonstrated that U2AF1 mutation impairs the differentiation of erythrocytes and granulocytes, but the impact on megakaryocytes (MKs) remains unclear. Here, by integrating data from MDS patients and cell lines with U2AF1 mutations, we determined that U2AF1 mutations are associated with dysmegakaryopoiesis, induce the generation of abnormal MKs, especially micro-MKs, and induce significant thrombocytopenia.
View Article and Find Full Text PDFU2AF1 mutations rescue deleterious exon skipping induced by KRAS mutations.
bioRxiv
March 2025
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA.
The mechanisms by which somatic mutations of splicing factors, such as U2AF1 in lung adenocarcinoma, contribute to cancer pathogenesis are not well understood. Here, we used prime editing to modify the endogenous gene in lung adenocarcinoma cells and assessed the resulting impact on alternative splicing. These analyses identified as a key target modulated by U2AF1.
View Article and Find Full Text PDFMicrosatellite instability at U2AF-binding polypyrimidic tract sites perturbs alternative splicing during colorectal cancer initiation.
Genome Biol
August 2024
Sorbonne Université, INSERM, Unité Mixte de Recherche Scientifique 938 and SIRIC CURAMUS, Centre de Recherche Saint-Antoine, Equipe Instabilité Des Microsatellites Et Cancer, Equipe Labellisée Par La Ligue Nationale Contre Le Cancer, 75012, Paris, France.
Article Synopsis
- Microsatellite instability (MSI), often linked to mismatch repair deficiency in colorectal cancer (CRC), leads to numerous noncoding DNA mutations, particularly affecting RNA splicing sites.
- This research shows that these noncoding mutations happen early in tumor development, even before the cancer cells become mutated in their coding regions, and are associated with altered splicing patterns in mRNA.
- The altered RNA splicing impacts cellular differentiation and promotes the initiation of MSI CRC, indicating that these noncoding changes are significant for cancer progression before traditional coding mutations occur.
Mutant U2AF1-Induced Mis-Splicing of mRNA Translation Genes Confers Resistance to Chemotherapy in Acute Myeloid Leukemia.
Cancer Res
May 2024
Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Unlabelled: Patients with primary refractory acute myeloid leukemia (AML) have a dismal long-term prognosis. Elucidating the resistance mechanisms to induction chemotherapy could help identify strategies to improve AML patient outcomes. Herein, we retrospectively analyzed the multiomics data of more than 1,500 AML cases and found that patients with spliceosome mutations had a higher risk of developing refractory disease.
View Article and Find Full Text PDFMyelodysplastic neoplasm-associated U2AF1 mutations induce host defense defects by compromising neutrophil chemotaxis.
Leukemia
October 2023
Department of Immunology and Genomic Medicine, National Jewish Health, Denver, CO, USA.
Myelodysplastic neoplasm (MDS) is a hematopoietic stem cell disorder that may evolve into acute myeloid leukemia. Fatal infection is among the most common cause of death in MDS patients, likely due to myeloid cell cytopenia and dysfunction in these patients. Mutations in genes that encode components of the spliceosome represent the most common class of somatically acquired mutations in MDS patients.
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