GSE134843
RNA seq analysis of SHP099 treated Leukemic Cells Expressing Genetic and Epigenetic Mutations
10 to 30% normal karyotype acute myeloid leukemia (AML) patients express mutations in regulators of DNA methylation such as TET2 or DNMT3A in conjunction with activating mutation in receptor tyrosine kinase, FLT3, which can be present in up to 50% of normal karyotype AML patients. These patients have poor prognosis since 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 SHP2, a protein tyrosine phosphatase, essential for cytokine receptor signaling, including FLT3, by a small molecule allosteric inhibitor, SHP099, impairs growth and induces differentiation of leukemic cells without impacting normal hematopoietic cells. We further show that SHP099 normalizes gene expression program associated with increased cell proliferation and self-renewal in leukemic cells by down regulating the Myc signature. Our results provide a new and more effective target for treating a subset of AML patients bearing a combination of genetic and epigenetic mutations.  Overall design: To elucidate the mechanism of action of SHP099 on leukemic myeloid cells, lineage depleted cells were isolated from bone marrow of Tet2-/-Flt3ITD mice and cultured in presence of cytokines (SCF, IL-6, IL-3) to expand primitive myeloid committed cells. The cells from Tet2-/-Flt3ITD mice were treated with SHP099 or vehicle for 24 hr and RNA-seq was performed on samples from 3 independent cultures established from individual mice. For comparison of gene expression profile, lineage depleted wild type (WT) cells were similarly isolated and cultured.