Department of Pathology, Massachusetts General Research Institute, Boston, MA, 02114, USA.
Center of Cancer Research, Massachusetts General Hospital, Charlestown, MA, 02129, USA.
Leukemia. 2021 Mar;35(3):679-690. doi: 10.1038/s41375-020-0937-3. Epub 2020 Jun 30.
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.
T 细胞急性淋巴细胞白血病（T-ALL）是一种侵袭性的胸苷细胞恶性肿瘤，主要由 NOTCH/MYC 通路驱动。然而，还需要额外的致癌驱动因素来实现转化。在这里，我们确定蛋白酪氨酸磷酸酶 4A3（PRL3）是 T-ALL 中的协同致癌驱动因子。PRL3 在很大一部分原发性人类 T-ALL 中表达，并且通常与 MYC 共扩增。PRL3 还与 MYC 协同作用，在转基因斑马鱼中引发早发性 ALL，并且是人类 T-ALL 生长和维持所必需的。质谱磷酸化蛋白质组学分析和机制研究表明，PRL3 抑制下游 T 细胞磷酸化信号通路，包括 VAV1 调节的信号通路，并随后抑制白血病细胞的凋亡。总之，我们的研究确定了 PRL3 作为人类 T-ALL 中协同致癌驱动因子的新作用，并表明靶向 PRL3 磷酸酶的治疗可能是 T-ALL 的一种有用治疗策略。
