Inhibition of the Gab2/PI3K/mTOR signaling ameliorates myeloid malignancy caused by Ptpn11 (Shp2) gain-of-function mutations.
Inhibition of the Gab2/PI3K/mTOR signaling ameliorates myeloid malignancy caused by Ptpn11 (Shp2) gain-of-function mutations.
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作者：
Liu W;Yu WM;Zhang J;Chan RJ;Loh ML;Zhang Z;Bunting KD;Qu CK
在参与多种细胞信号传导过程的蛋白酪氨酸磷酸酶PTPN11（SHP2）中，诸如E76K和D61Y等激活突变与35%的幼年型粒单核细胞白血病（JMML）患者相关，JMML是一种侵袭性的儿童骨髓增殖性肿瘤（MPN）。目前仍缺乏针对这种恶性肿瘤的有效治疗干预措施。在此我们表明，白血病相关的突变型Shp2与Gab2（一种对细胞因子诱导的PI3K/Akt信号传导很重要的支架蛋白）之间的相互作用增强，并且在Ptpn11E76K/+白血病细胞中mTOR通路升高。重要的是，在Ptpn11E76K/+/Gab2 -/-双突变小鼠中，由Ptpn11E76K/+突变诱导的MPN显著减弱——这些双突变体中髓系细胞的过度产生得到缓解，脾肿大减轻，非造血器官中的髓系细胞浸润减少。通过消耗Gab2，干细胞的过度髓系分化也恢复正常。双突变小鼠中MPN的急性白血病进展减缓，因此它们的生存期大大延长。此外，用雷帕霉素（一种特异性且强效的mTOR抑制剂）治疗Ptpn11E76K/+小鼠可减轻MPN表型。总之，这项研究揭示了Gab2/PI3K/mTOR通路在介导PTPN11功能获得性突变的致病信号传导中的重要作用，以及雷帕霉素对PTPN11突变相关JMML的治疗潜力。
Activating mutations, such as E76K and D61Y, in PTPN11 (SHP2), a protein tyrosine phosphatase implicated in multiple cell signaling processes, are associated with 35% of patients with juvenile myelomonocytic leukemia (JMML), an aggressive childhood myeloproliferative neoplasm (MPN). Effective therapeutic interventions for this malignancy are still lacking. Here we show that the interaction between leukemia-associated mutant Shp2 and Gab2, a scaffolding protein important for cytokine-induced PI3K/Akt signaling, was enhanced, and that the mTOR pathway was elevated in Ptpn11E76K/+ leukemic cells. Importantly, MPN induced by the Ptpn11E76K/+ mutation was markedly attenuated in Ptpn11E76K/+/Gab2−/− double mutant mice — Overproduction of myeloid cells was alleviated, splenomegaly was diminished, and myeloid cell infiltration in non-hematopoietic organs was decreased in these double mutants. Excessive myeloid differentiation of stem cells was also normalized by depletion of Gab2. Acute leukemia progression of MPN was reduced in the double mutant mice, and as such, their survival was much prolonged. Furthermore, treatment of Ptpn11E76K/+ mice with Rapamycin, a specific and potent mTOR inhibitor, mitigated MPN phenotypes. Collectively, this study reveals an important role of the Gab2/PI3K/mTOR pathway in mediating the pathogenic signaling of the PTPN11 gain-of-function mutations, and a therapeutic potential of Rapamycin for PTPN11 mutation-associated JMML.