Expression of mutant Asxl1 perturbs hematopoiesis and promotes susceptibility to leukemic transformation
| Autor: | Kimihito Cojin Kawabata, Hiroaki Honda, Makoto Saika, Takeshi Fujino, Norimasa Yamasaki, Hwei-Fang Tien, Yasunori Ota, Yasuyuki Sera, Akinori Kanai, Toshio Kitamura, Sayuri Horikawa, Daichi Inoue, Alessandro Pastore, Hsin-An Hou, Shuhei Asada, Y Hayashi, Reina Nagase, Susumu Goyama, Reina Takeda, Omar Abdel-Wahab |
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| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Adult Myeloid Transcription Genetic Immunology Mutant Biology Article Epigenesis Genetic Insertional mutagenesis Histones 03 medical and health sciences chemistry.chemical_compound Mice medicine Immunology and Allergy Animals Humans Gene Knock-In Techniques Research Articles Leukemia Base Sequence Gene Expression Regulation Leukemic Genome Human Hematopoietic Stem Cell Transplantation medicine.disease Hematopoietic Stem Cells Hematopoiesis Transplantation Repressor Proteins Haematopoiesis Leukemia Myeloid Acute 030104 developmental biology medicine.anatomical_structure Cell Transformation Neoplastic Phenotype RUNX1 chemistry Mutagenesis Myelodysplastic Syndromes Mutation Cancer research Chromatin immunoprecipitation Protein Binding |
| Zdroj: | The Journal of Experimental Medicine |
| ISSN: | 1540-9538 0022-1007 |
| Popis: | Nagase and Inoue et al. generated a novel Asxl1 mutant mouse model to mimic clonal hematopoiesis and myelodysplastic syndromes caused by ASXL1 mutations and elucidated the effects of mutant versus wild-type ASXL1 on hematopoiesis, gene expression, and chromatin state. Additional sex combs like 1 (ASXL1) is frequently mutated in myeloid malignancies and clonal hematopoiesis of indeterminate potential (CHIP). Although loss of ASXL1 promotes hematopoietic transformation, there is growing evidence that ASXL1 mutations might confer an alteration of function. In this study, we identify that physiological expression of a C-terminal truncated Asxl1 mutant in vivo using conditional knock-in (KI) results in myeloid skewing, age-dependent anemia, thrombocytosis, and morphological dysplasia. Although expression of mutant Asxl1 altered the functions of hematopoietic stem cells (HSCs), it maintained their survival in competitive transplantation assays and increased susceptibility to leukemic transformation by co-occurring RUNX1 mutation or viral insertional mutagenesis. KI mice displayed substantial reductions in H3K4me3 and H2AK119Ub without significant reductions in H3K27me3, distinct from the effects of Asxl1 loss. Chromatin immunoprecipitation followed by next-generation sequencing analysis demonstrated opposing effects of wild-type and mutant Asxl1 on H3K4me3. These findings reveal that ASXL1 mutations confer HSCs with an altered epigenome and increase susceptibility for leukemic transformation, presenting a novel model for CHIP. |
| Databáze: | OpenAIRE |
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