|
| Status |
Public on Sep 01, 2018 |
| Title |
Genetic and epigenetic evolution as a contributor to WT1-mutant leukemogenesis |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
|
| Summary |
Genetic studies have identified recurrent somatic mutations in Acute Myeloid Leukemia (AML) patients, including in WT1 (Wilms’ tumor gene 1). The molecular mechanisms by which WT1 mutations contribute to leukemogenesis have not yet been fully elucidated. We investigated the role of Wt1 gene dosage in steady state and pathologic hematopoiesis. Wt1 heterozygous loss enhanced stem cell self-renewal in an age-dependent manner, with increased stem cell function over time and age-dependent leukemic transformation. Wt1-haploinsufficient leukemias were characterized by progressive genetic and epigenetic alterations, including in known leukemia disease alleles, demonstrating a requirement for additional events to promote hematopoietic transformation. Consistent with this observation, we found that Wt1 haploinsufficiency cooperates with Flt3-ITD mutation to induce fully penetrant AML. Our studies provide insight into mechanisms of Wt1-loss in leukemogenesis and into the evolutionary events required to induce transformation of Wt1-haploinsufficient stem/progenitor cells.
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| |
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| Overall design |
RNA-seq of sorted myeloid progenitors from Mx+ Wt1fl/+ mice of different ages compared to age-matched control counterparts
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| |
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| Contributor(s) |
Pronier E, Koche RP, Levine RL |
| Citation(s) |
30064973 |
| |
| Submission date |
Jan 31, 2018 |
| Last update date |
Jan 08, 2020 |
| Contact name |
Richard Koche |
| E-mail(s) |
kocher@mskcc.org
|
| Organization name |
Memorial Sloan Kettering Cancer Center
|
| Street address |
417 E. 68th St.
|
| City |
New York |
| State/province |
New York |
| ZIP/Postal code |
10065 |
| Country |
USA |
| |
|
| Platforms (1) |
| GPL17021 |
Illumina HiSeq 2500 (Mus musculus) |
|
| Samples (12)
|
|
| Relations |
| BioProject |
PRJNA432423 |
| SRA |
SRP131916 |
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