SHP2 inhibition reduces leukemogenesis in models of combined genetic and epigenetic mutations
Ruchi Pandey, … , Chi Zhang, Reuben Kapur
Ruchi Pandey, … , Chi Zhang, Reuben Kapur
Published November 4, 2019
Citation Information: J Clin Invest. 2019. https://doi.org/10.1172/JCI130520.
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Categories: Concise Communication Hematology Oncology

SHP2 inhibition reduces leukemogenesis in models of combined genetic and epigenetic mutations

Abstract

In patients with acute myeloid leukemia (AML), 10% to 30% with the normal karyotype express mutations in regulators of DNA methylation, such as TET2 or DNMT3A, in conjunction with activating mutation in the receptor tyrosine kinase FLT3. These patients have a poor prognosis because they do not respond well to established therapies. Here, utilizing mouse models of AML that recapitulate cardinal features of the human disease and bear a combination of loss-of-function mutations in either Tet2 or Dnmt3a along with expression of Flt3ITD, we show that inhibition of the protein tyrosine phosphatase SHP2, which is essential for cytokine receptor signaling (including FLT3), by the small molecule allosteric inhibitor SHP099 impairs growth and induces differentiation of leukemic cells without impacting normal hematopoietic cells. We also show that SHP099 normalizes the gene expression program associated with increased cell proliferation and self-renewal in leukemic cells by downregulating the Myc signature. Our results provide a new and more effective target for treating a subset of patients with AML who bear a combination of genetic and epigenetic mutations.

Authors

Ruchi Pandey, Baskar Ramdas, Changlin Wan, George Sandusky, Morvarid Mohseni, Chi Zhang, Reuben Kapur

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Figure 1

Effect of SHP099 treatment on leukemic Tet2–/–Flt3ITD cells.

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Effect of SHP099 treatment on leukemic Tet2–/–Flt3ITD cells. Bone marrow...
Bone marrow cells from Boy/J (CD45.1+) and Tet2–/–Flt3ITD (CD45.2+) mice were transplanted in irradiated F1 (CD45.1+CD45.2+) mice followed by treatment with vehicle (n = 5) or SHP099 (n = 6) for 4 weeks. (A) Number of WBCs, neutrophils, and monocytes in the PB. (B) Percentage CD45.2+CD45.1– cells in PB. (C) Representative flow cytometric profiles of Gr1 and CD11b expression in PB cells gated on CD45.1–. (D) Quantification of Gr1–CD11b+ and Gr1+CD11b+ cells within CD45.1– gate. (E) Image of spleens from treated mice. (F) Quantification of spleen weight. (G) Representative H&E-stained images from spleen and femur of treated mice, acquired at ×20. (H) Representative flow plots of CD11b and c-KIT expression in CD45.1–-gated spleen cells. (I) Representative flow plots of CD48 and CD150 expression in CD45.1–lin–Sca1+C-KIT+ (leukemic LSK) cells. (J) Quantification of HPC1 (CD48+CD150–) and HPC2 (CD48+CD150+) cells therein. Data points are values from individual mice in each group from 1 of the 2 representative experiments. Median value for each group is indicated with interquartile range. *P < 0.05, **P < 0.01; Student’s t test with Welch’s correction for unequal variance.