Open AccessPRL3 enhances T-cell acute lymphoblastic leukemia growth through suppressing T-cell signaling pathways and apoptosis
Author(s) -
Elaine G. Garcia,
Alexandra Veloso,
Mariana L. Oliveira,
James Allen,
Siebe Loontiens,
Dalton C. Brunson,
Daniel Do,
Chuan Yan,
Robert T. Morris,
Sowmya Iyer,
Sara P. Garcia,
Nicolae Iftimia,
Wouder Van Loocke,
Filip Matthijssens,
Karin M. McCarthy,
João T. Barata,
Franki Speleman,
Tom Taghon,
Alejandro Gutiérrez,
Pieter Van Vlierberghe,
Wilhelm Haas,
Jessica S. Blackburn,
Dm M. Langenau
Publication year - 2020
Publication title -
leukemia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.539
H-Index - 192
eISSN - 1476-5551
pISSN - 0887-6924
DOI - 10.1038/s41375-020-0937-3
Subject(s) - zebrafish , biology , cancer research , protein tyrosine phosphatase , signal transduction , apoptosis , leukemia , cell growth , phosphorylation , notch signaling pathway , microbiology and biotechnology , immunology , genetics , gene
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.