Transcriptional control and signal transduction, cell cycle

Inhibition of the Gab2/PI3K/mTOR signaling ameliorates myeloid malignancy caused by Ptpn11 (Shp2) gain-of-function mutations


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). 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 nonhematopoietic 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.

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We are grateful to Dr Toshio Hirano for Gab2+/− mice. This work was supported by National Institutes of Health grants HL130995 and DK092722, and a Hyundai Hope on Wheels scholar grant (to CKQ).

Author contributions

WL, WMY, and JZ conducted the research and summarized the data. RJC, MLL, ZZ, and KDB provided critical reagents, discussed the work and edited the manuscript. CKQ designed the experiments and provided technical training to the first three authors. WL and CKQ wrote the manuscript.

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Correspondence to C-K Qu.

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The authors declare no conflict of interest.

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Supplementary Information accompanies this paper on the Leukemia website

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Liu, W., Yu, W., Zhang, J. et al. Inhibition of the Gab2/PI3K/mTOR signaling ameliorates myeloid malignancy caused by Ptpn11 (Shp2) gain-of-function mutations. Leukemia 31, 1415–1422 (2017).

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