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| Status |
Public on Jun 05, 2020 |
| Title |
RUNX2 is a dependency factor in immature and KMT2A-rearranged T-cell acute lymphoblastic leukemia [KMT2A-MLLT1_ Runx2 ko RNA-seq] |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematologic malignancy with a high incidence of relapse. Here we show that Runt-related transcription factor 2, RUNX2 is upregulated in high-risk T-ALL with KMT2A rearrangements (KMT2A-R) or immature phenotype. In KMT2A-R cells, we identified RUNX2 as a direct target of the KMT2A chimeras, while it reciprocally binds the KMT2A promoter, establishing a regulatory feed-forward mechanism. Notably, RUNX2 is required for survival in immature and KMT2A-R T-ALL in vitro and in vivo. We report a direct transcriptional regulation of CXCR4 signaling by RUNX2, which thereby promotes cell migration and adhesion. Functionally, RUNX2 impacts T-ALL cell homing and exacerbates T-ALL progression to medullary and extramedullary sites. We demonstrate that RUNX2 enables these energy-demanding processes by increasing metabolic activity in T-ALL cells through positive regulation of both glycolysis and oxidative phosphorylation. Concurrently, RUNX2 upregulation results in increased mitochondrial dynamics and biogenesis in T-ALL cells. As a proof of concept, immature and KMT2A-R T-ALL cells are vulnerable to pharmacological targeting of the interaction of RUNX2 with its co-factor CBFβ. In conclusion, we identify RUNX2 a dependency factor in immature and KMT2A-R T-ALL that regulates cell metabolism and disease progression
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| Overall design |
Examination of transcriptional changes upon in Runx2fl/fl;CreER T2tg mouse bone marrow progenitor compared to cells that were transformed in vitro by KMT2A-MLLT1 retroviral transduction. In vitro transformation of mouse progenitor cells was performed on lineage depleted (Runx2fl/fl CreErt2tg/+) BM cells that were transduced with KMT2A-MLLT1-eGFP expressing retrovirus. To achieve complete Runx2 knockout, cells were treated with 400 nM 4-hydroxytamoxifen (4-OHT) for 24 hours.
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| Contributor(s) |
Matthijssens F, Van Vlierberghe P |
| Citation(s) |
33555272 |
| |
| Submission date |
Jun 04, 2020 |
| Last update date |
Feb 10, 2021 |
| Contact name |
Filip Matthijssens |
| E-mail(s) |
Filip.Matthijssens@UGent.be
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| Phone |
093325268
|
| Organization name |
Ghent University
|
| Department |
Biomolecular Medicine
|
| Lab |
Lab of normal and malignant hematopoesis
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| Street address |
Corneel Heymanslaan 10
|
| City |
Ghent |
| State/province |
België |
| ZIP/Postal code |
9000 |
| Country |
Belgium |
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| Platforms (1) |
| GPL19057 |
Illumina NextSeq 500 (Mus musculus) |
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| Samples (9)
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| This SubSeries is part of SuperSeries: |
| GSE151823 |
RUNX2 is a dependency factor in immature and KMT2A-rearranged T-cell acute lymphoblastic leukemia |
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| Relations |
| BioProject |
PRJNA637337 |
| SRA |
SRP265980 |
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