Department of Hematology and Oncology, Chongqing University Three Gorges Hospital, Chongqing, China.
Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL.
Blood. 2023 Jan 19;141(3):244-259. doi: 10.1182/blood.2022016580.
Acute myeloid leukemia (AML) is an aggressive blood cancer with poor prognosis. FMS-like tyrosine kinase receptor-3 (FLT3) is one of the major oncogenic receptor tyrosine kinases aberrantly activated in AML. Although protein tyrosine phosphatase PRL2 is highly expressed in some subtypes of AML compared with normal human hematopoietic stem and progenitor cells, the mechanisms by which PRL2 promotes leukemogenesis are largely unknown. We discovered that genetic and pharmacological inhibition of PRL2 significantly reduce the burden of FLT3-internal tandem duplications-driven leukemia and extend the survival of leukemic mice. Furthermore, we found that PRL2 enhances oncogenic FLT3 signaling in leukemia cells, promoting their proliferation and survival. Mechanistically, PRL2 dephosphorylates the E3 ubiquitin ligase CBL at tyrosine 371 and attenuates CBL-mediated ubiquitination and degradation of FLT3, leading to enhanced FLT3 signaling in leukemia cells. Thus, our study reveals that PRL2 enhances oncogenic FLT3 signaling in leukemia cells through dephosphorylation of CBL and will likely establish PRL2 as a novel druggable target for AML.
急性髓系白血病（AML）是一种预后不良的侵袭性血液癌症。FMS 样酪氨酸激酶受体 3（FLT3）是 AML 中异常激活的主要致癌受体酪氨酸激酶之一。虽然与正常人类造血干/祖细胞相比，蛋白酪氨酸磷酸酶 PRL2 在某些 AML 亚型中高度表达，但 PRL2 促进白血病发生的机制在很大程度上尚不清楚。我们发现，PRL2 的遗传和药理学抑制可显著减轻由 FLT3 内部串联重复驱动的白血病负担，并延长白血病小鼠的存活期。此外，我们发现 PRL2 增强了白血病细胞中的致癌性 FLT3 信号，促进其增殖和存活。从机制上讲，PRL2 使 E3 泛素连接酶 CBL 在酪氨酸 371 处去磷酸化，并减弱 CBL 介导的 FLT3 的泛素化和降解，从而导致白血病细胞中增强的 FLT3 信号。因此，我们的研究表明，PRL2 通过 CBL 的去磷酸化增强了白血病细胞中的致癌性 FLT3 信号，这可能将 PRL2 确立为 AML 的新型可靶向治疗靶标。
