CBFβ-MYH11 interferes with megakaryocyte differentiation via modulating a gene program that includes GATA2 and KLF1
| Autor: | Marten Hansen, Esther Tijchon, Laura Jussen, Pascal W. T. C. Jansen, Luan Nguyen, Guoqiang Yi, Jonathan Bond, Michiel Vermeulen, Bert A. van der Reijden, Joost H.A. Martens, Emile van den Akker, Maaike G.J.M. van Bergen, Amit Mandoli, Gaëlle Cordonnier, Bowon Kim |
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| Přispěvatelé: | Landsteiner Laboratory |
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
Oncogene Proteins
Fusion Transcription Genetic Megakaryocyte differentiation Cellular differentiation Cancer development and immune defence Radboud Institute for Molecular Life Sciences [Radboudumc 2] Kruppel-Like Transcription Factors Biology lcsh:RC254-282 Article Epigenesis Genetic Thrombopoiesis 03 medical and health sciences 0302 clinical medicine Erythroid Cells Cell Line Tumor hemic and lymphatic diseases MYH11 Humans Erythropoiesis Molecular Biology Cell Proliferation Regulation of gene expression Gene knockdown Binding Sites Gene Expression Regulation Leukemic Proteomics and Chromatin Biology Gene Expression Profiling GATA2 Cell Differentiation Hematology lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens Cell biology GATA2 Transcription Factor Haematopoiesis Leukemia Myeloid Acute Oncology 030220 oncology & carcinogenesis Gene Knockdown Techniques Megakaryocytes 030215 immunology Protein Binding |
| Zdroj: | Blood Cancer Journal, Vol 9, Iss 3, Pp 1-13 (2019) Blood Cancer Journal, 9, 33 Blood Cancer Journal Blood cancer journal, 9(3):33. Nature Publishing Group Blood Cancer Journal, 9, 3, pp. 33 |
| ISSN: | 2044-5385 |
| DOI: | 10.1038/s41408-019-0194-8 |
| Popis: | The inv(16) acute myeloid leukemia-associated CBFβ-MYH11 fusion is proposed to block normal myeloid differentiation, but whether this subtype of leukemia cells is poised for a unique cell lineage remains unclear. Here, we surveyed the functional consequences of CBFβ-MYH11 in primary inv(16) patient blasts, upon expression during hematopoietic differentiation in vitro and upon knockdown in cell lines by multi-omics profiling. Our results reveal that primary inv(16) AML cells share common transcriptomic signatures and epigenetic determiners with megakaryocytes and erythrocytes. Using in vitro differentiation systems, we reveal that CBFβ-MYH11 knockdown interferes with normal megakaryocyte maturation. Two pivotal regulators, GATA2 and KLF1, are identified to complementally occupy RUNX1-binding sites upon fusion protein knockdown, and overexpression of GATA2 partly induces a gene program involved in megakaryocyte-directed differentiation. Together, our findings suggest that in inv(16) leukemia, the CBFβ-MYH11 fusion inhibits primed megakaryopoiesis by attenuating expression of GATA2/KLF1 and interfering with a balanced transcriptional program involving these two factors. |
| Databáze: | OpenAIRE |
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