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 December 2, 2019; First published November 4, 2019
Citation Information: J Clin Invest. 2019;129(12):5468-5473. https://doi.org/10.1172/JCI130520.
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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 3

Effect of SHP099 treatment on bone marrow stem cells in Dnmt3a+/–Flt3ITD-induced AML model.

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Effect of SHP099 treatment on bone marrow stem cells in Dnmt3a+/–Flt3ITD...
Analysis of bone marrow cells from mice transplanted with Dnmt3a+/–Flt3ITD (CD45.2+) and Boy/J (CD45.1+) cells and treated with vehicle or SHP099 as in Figure 2. (A) Representative flow plots showing the analysis strategy (top, vehicle-treated mice; bottom, SHP099-treated mice). Quantification of (B) percentage of CD45.2+ cells, (C) percentage of lin– cells, (D) percentage of LSK cells in the leukemic (CD45.2+) compartment and (E) percentage of HPC1 (lin–Sca1+KIT+CD48+CD150–) within the CD45.2+LSK gate. Data points shown are values from individual mice in each group. Median value for each group is indicated with the interquartile range. *P < 0.05, **P < 0.01; Student’s t test with Welch’s correction for unequal variance.