PLX148700

GSE134843: RNA seq analysis of SHP099 treated Leukemic Cells Expressing Genetic and Epigenetic Mutations

• Organsim mouse
• Type RNASEQ
• Target gene
• Project ARCHS4

10 to 30% normal karyotype acute myeloid leukemia (AML) patients express mutations in regulators of DNA methylation such asTET2orDNMT3Ain 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 eitherTet2orDnmt3aalong with expression ofFlt3ITD, 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 theMycsignature. Our results provide a new and more effective target for treating a subset of AML patients bearing a combination of genetic and epigenetic mutations. SOURCE: Reuben Kapur (rkapur@iupui.edu) - INDIANA UNIVERSITY