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Generation and Characterization of Induced Pluripotent Stem Cells Carrying An <italic>ASXL1</italic> Mutation.
- Source :
-
Stem Cell Reviews & Reports . Jun2024, p1-13. - Publication Year :
- 2024
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Abstract
- Additional sex combs-like 1 (<italic>ASXL1</italic>) is an epigenetic modulator frequently mutated in myeloid malignancies, generally associated with poor prognosis. Current models for <italic>ASXL1</italic>-mutated diseases are mainly based on the complete deletion of <italic>Asxl1</italic> or overexpression of C-terminal truncations in mice models. However, these models cannot fully recapitulate the pathogenesis of myeloid malignancies. Patient-derived induced pluripotent stem cells (iPSCs) provide valuable disease models that allow us to understand disease-related molecular pathways and develop novel targeted therapies. Here, we generated iPSCs from a patient with myeloproliferative neoplasm carrying a heterozygous <italic>ASXL1</italic> mutation<italic>.</italic> The iPSCs we generated exhibited the morphology of pluripotent cells, highly expressed pluripotent markers, excellent differentiation potency in vivo, and normal karyotype. Subsequently, iPSCs with or without <italic>ASXL1</italic> mutation were induced to differentiate into hematopoietic stem/progenitor cells, and we found that <italic>ASXL1</italic> mutation led to myeloid-biased output and impaired erythroid differentiation. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses showed that terms related to embryonic development, myeloid differentiation, and immune- and neural-related processes were most enriched in the differentially expressed genes. Western blot demonstrated that the global level of H2AK119ub was significantly decreased when mutant <italic>ASXL1</italic> was present. Chromatin Immunoprecipitation Sequencing showed that most genes associated with stem cell maintenance were upregulated, whereas occupancies of H2AK119ub around these genes were significantly decreased. Thus, the iPSC model carrying <italic>ASXL1</italic> mutation could serve as a potential tool to study the pathogenesis of myeloid malignancies and to screen targeted therapy for patients.Graphical Abstract: Additional sex combs-like 1 (<italic>ASXL1</italic>) is an epigenetic modulator frequently mutated in myeloid malignancies, generally associated with poor prognosis. Current models for <italic>ASXL1</italic>-mutated diseases are mainly based on the complete deletion of <italic>Asxl1</italic> or overexpression of C-terminal truncations in mice models. However, these models cannot fully recapitulate the pathogenesis of myeloid malignancies. Patient-derived induced pluripotent stem cells (iPSCs) provide valuable disease models that allow us to understand disease-related molecular pathways and develop novel targeted therapies. Here, we generated iPSCs from a patient with myeloproliferative neoplasm carrying a heterozygous <italic>ASXL1</italic> mutation<italic>.</italic> The iPSCs we generated exhibited the morphology of pluripotent cells, highly expressed pluripotent markers, excellent differentiation potency in vivo, and normal karyotype. Subsequently, iPSCs with or without <italic>ASXL1</italic> mutation were induced to differentiate into hematopoietic stem/progenitor cells, and we found that <italic>ASXL1</italic> mutation led to myeloid-biased output and impaired erythroid differentiation. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses showed that terms related to embryonic development, myeloid differentiation, and immune- and neural-related processes were most enriched in the differentially expressed genes. Western blot demonstrated that the global level of H2AK119ub was significantly decreased when mutant <italic>ASXL1</italic> was present. Chromatin Immunoprecipitation Sequencing showed that most genes associated with stem cell maintenance were upregulated, whereas occupancies of H2AK119ub around these genes were significantly decreased. Thus, the iPSC model carrying <italic>ASXL1</italic> mutation could serve as a potential tool to study the pathogenesis of myeloid malignancies and to screen targeted therapy for patients. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 15508943
- Database :
- Academic Search Index
- Journal :
- Stem Cell Reviews & Reports
- Publication Type :
- Academic Journal
- Accession number :
- 177922964
- Full Text :
- https://doi.org/10.1007/s12015-024-10737-z