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CBFβ-MYH11 interferes with megakaryocyte differentiation via modulating a gene program that includes GATA2 and KLF1
- Source :
- 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
- Publication Year :
- 2019
- Publisher :
- Nature Publishing Group, 2019.
-
Abstract
- 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.
- Subjects :
- 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
Subjects
Details
- Language :
- English
- ISSN :
- 20445385
- Volume :
- 9
- Issue :
- 3
- Database :
- OpenAIRE
- Journal :
- Blood Cancer Journal
- Accession number :
- edsair.doi.dedup.....700acae5b654a82e9a9bdd5289960f87