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| Status |
Public on Mar 22, 2019 |
| Title |
CBFβ-MYH11 fusion blocks hematopoietic differentiation via repression of a GATA2 gene program |
| Organism |
Homo sapiens |
| Experiment type |
Genome binding/occupancy profiling by high throughput sequencing
Expression profiling by high throughput sequencing
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| Summary |
The CBFβ-MYH11 fusion generated by inv(16) aberration is proposed to block normal myeloid differentiation, but whether this subtype of leukemia cells is poised for an unique cell lineage remains unclear. Here, we surveyed the functional consequences of CBFβ-MYH11 in inv(16) patient blasts and two inducible systems by multi-omics profiling. The primary inv(16) cells stay closer with megakaryocyte and erythrocyte lineages along the cell differentiation trajectory, and share common transcriptomic signatures and epigenetic determiners. Using in vitro differentiation systems, we reveal that CBFβ-MYH11 knockdown establishes normal endomitosis-related processes, which are crucial for megakaryocyte maturation. Two pivotal regulators, GATA2 and KLF1, are identified to complementally occupy RUNX1 binding sites upon the fusion protein knockdown. Overexpression of GATA2 partly restores megakaryocyte directed differentiation suppressed by CBFβ-MYH11, and additional factors like KLF1 and EGR1 might be required to coordinately prevent CFB-MYH11 leukemogenesis. Together, our findings suggest that in inv(16) leukemia, the CBFβ-MYH11 fusion inhibits primed megakaryopoiesis by interfering with a balanced transcriptional program involving GATA2 and KLF1.
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| Overall design |
ChIP-seq and RNA-seq using an AML cell line harbouring a dox inducible CBFB-MYH11 knockdown construct (induction using 600 ng/ml dox for 72 hours)
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| Contributor(s) |
Yi G, Mandoli A, Jussen L, Tijchon E, Kim B, Cordonnier G, Bond J, Martens J |
| Citation(s) |
30850577 |
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| Submission date |
Jul 16, 2018 |
| Last update date |
Nov 11, 2021 |
| Contact name |
Joost Martens |
| E-mail(s) |
joost.martens@ru.nl
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| Phone |
0243780645
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| Organization name |
Radboud University
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| Department |
RIMLS
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| Lab |
Molecular Biology
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| Street address |
Geert Grooteplein 28
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| City |
Nijmegen |
| State/province |
Nederland |
| ZIP/Postal code |
6525GA |
| Country |
Netherlands |
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| Platforms (2) |
| GPL11154 |
Illumina HiSeq 2000 (Homo sapiens) |
| GPL18573 |
Illumina NextSeq 500 (Homo sapiens) |
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| Samples (17)
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| Relations |
| BioProject |
PRJNA481263 |
| SRA |
SRP153823 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE117138_RAW.tar |
2.0 Gb |
(http)(custom) |
TAR (of BW) |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data provided as supplementary file |
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