期刊
LEUKEMIA
卷 35, 期 3, 页码 679-690出版社
SPRINGERNATURE
DOI: 10.1038/s41375-020-0937-3
关键词
-
资金
- NIH [R01CA211734, R37CA227656, CA193651]
- MGH Research Scholar Award
- Alex Lemonade Stand Foundation
- V Foundation for Cancer Research
- Boston Children's Hospital
- Research Foundation Flanders
- 'Kom op tegen Kanker' (Stand up to Cancer)
- Ghent University Special Research Fund
- MGH Pathology CNY Flow Cytometry Core shared instrumentation grant [1S10RR023440-01A1]
The study identifies PRL3 as a collaborating oncogenic driver in T-ALL, which synergizes with MYC to promote leukemia development and suppress apoptosis in cells. By suppressing downstream phosphorylation signaling pathways, PRL3's role in T-ALL is elucidated.
T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive malignancy of thymocytes and is largely driven by the NOTCH/MYC pathway. Yet, additional oncogenic drivers are required for transformation. Here, we identify protein tyrosine phosphatase type 4 A3 (PRL3) as a collaborating oncogenic driver in T-ALL. PRL3 is expressed in a large fraction of primary human T-ALLs and is commonly co-amplified with MYC. PRL3 also synergized with MYC to initiate early-onset ALL in transgenic zebrafish and was required for human T-ALL growth and maintenance. Mass-spectrometry phosphoproteomic analysis and mechanistic studies uncovered that PRL3 suppresses downstream T-cell phosphorylation signaling pathways, including those modulated by VAV1, and subsequently suppresses apoptosis in leukemia cells. Taken together, our studies have identified new roles for PRL3 as a collaborating oncogenic driver in human T-ALL and suggest that therapeutic targeting of the PRL3 phosphatase will likely be a useful treatment strategy for T-ALL.
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