Department of Hematology, Chongqing University Three Gorges Hospital, Chongqing, China.
Department of Medicine, Northwestern University, Chicago, Illinois.
Mol Cancer Res. 2024 Jan 2;22(1):94-103. doi: 10.1158/1541-7786.MCR-23-0115.
Receptor tyrosine kinase KIT is frequently activated in acute myeloid leukemia (AML). While high PRL2 (PTP4A2) expression is correlated with activation of SCF/KIT signaling in AML, the underlying mechanisms are not fully understood. We discovered that inhibition of PRL2 significantly reduces the burden of oncogenic KIT-driven leukemia and extends leukemic mice survival. PRL2 enhances oncogenic KIT signaling in leukemia cells, promoting their proliferation and survival. We found that PRL2 dephosphorylates CBL at tyrosine 371 and inhibits its activity toward KIT, leading to decreased KIT ubiquitination and enhanced AKT and ERK signaling in leukemia cells.
Our studies uncover a novel mechanism that fine-tunes oncogenic KIT signaling in leukemia cells and will likely identify PRL2 as a novel therapeutic target in AML with KIT mutations.
受体酪氨酸激酶 KIT 在急性髓系白血病（AML）中经常被激活。虽然高 PRL2（PTP4A2）表达与 AML 中 SCF/KIT 信号的激活相关，但潜在机制尚不完全清楚。我们发现抑制 PRL2 可显著降低致癌性 KIT 驱动的白血病负担并延长白血病小鼠的存活期。PRL2 增强白血病细胞中的致癌性 KIT 信号，促进其增殖和存活。我们发现 PRL2 将 CBL 在酪氨酸 371 上去磷酸化并抑制其对 KIT 的活性，导致 KIT 泛素化减少，以及白血病细胞中的 AKT 和 ERK 信号增强。
我们的研究揭示了一种调节白血病细胞中致癌性 KIT 信号的新机制，并可能将 PRL2 鉴定为具有 KIT 突变的 AML 的新型治疗靶点。
