CBFβ-MYH11 interferes with megakaryocyte differentiation via modulating a gene program that includes GATA2 and KLF1

Blood Cancer J. 2019 Mar 8;9(3):33. doi: 10.1038/s41408-019-0194-8.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Binding Sites
  • Cell Differentiation
  • Cell Line, Tumor
  • Cell Proliferation
  • Epigenesis, Genetic
  • Erythroid Cells / cytology
  • Erythroid Cells / metabolism
  • Erythropoiesis / genetics
  • GATA2 Transcription Factor / metabolism*
  • Gene Expression Profiling
  • Gene Expression Regulation, Leukemic*
  • Gene Knockdown Techniques
  • Humans
  • Kruppel-Like Transcription Factors / metabolism*
  • Leukemia, Myeloid, Acute / genetics
  • Leukemia, Myeloid, Acute / metabolism
  • Megakaryocytes / cytology
  • Megakaryocytes / metabolism*
  • Oncogene Proteins, Fusion / genetics*
  • Oncogene Proteins, Fusion / metabolism
  • Protein Binding
  • Thrombopoiesis
  • Transcription, Genetic


  • CBFbeta-MYH11 fusion protein
  • GATA2 Transcription Factor
  • GATA2 protein, human
  • Kruppel-Like Transcription Factors
  • Oncogene Proteins, Fusion
  • erythroid Kruppel-like factor