CBFß-MYH11 interferes with megakaryocyte differentiation via modulating a gene program that includes GATA2 and KLF1.
Blood Cancer J
; 9(3): 33, 2019 03 08.
Article
in En
| MEDLINE
| ID: mdl-30850577
ABSTRACT
The inv(16) acute myeloid leukemia-associated CBFß-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 CBFß-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 CBFß-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 CBFß-MYH11 fusion inhibits primed megakaryopoiesis by attenuating expression of GATA2/KLF1 and interfering with a balanced transcriptional program involving these two factors.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Megakaryocytes
/
Gene Expression Regulation, Leukemic
/
Oncogene Proteins, Fusion
/
GATA2 Transcription Factor
/
Kruppel-Like Transcription Factors
Type of study:
Prognostic_studies
Limits:
Humans
Language:
En
Journal:
Blood Cancer J
Year:
2019
Document type:
Article
Affiliation country:
Países Bajos