4.7 Article

PRL3 enhances T-cell acute lymphoblastic leukemia growth through suppressing T-cell signaling pathways and apoptosis

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LEUKEMIA
卷 35, 期 3, 页码 679-690

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SPRINGERNATURE
DOI: 10.1038/s41375-020-0937-3

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资金

  1. NIH [R01CA211734, R37CA227656, CA193651]
  2. MGH Research Scholar Award
  3. Alex Lemonade Stand Foundation
  4. V Foundation for Cancer Research
  5. Boston Children's Hospital
  6. Research Foundation Flanders
  7. 'Kom op tegen Kanker' (Stand up to Cancer)
  8. Ghent University Special Research Fund
  9. MGH Pathology CNY Flow Cytometry Core shared instrumentation grant [1S10RR023440-01A1]

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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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