We found a match
Your institution may have rights to this item. Sign in to continue.
- Title
SHP2 inhibition reduces leukemogenesis in models of combined genetic and epigenetic mutations.
- Authors
Pandey, Ruchi; Ramdas, Baskar; Changlin Wan; Sandusky, George; Mohseni, Morvarid; Chi Zhang; Kapur, Reuben; Wan, Changlin; Zhang, Chi
- 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.
- Subjects
GENETIC models; PRELEUKEMIA; PROTEIN-tyrosine phosphatase; ACUTE myeloid leukemia; CYTOKINE receptors; PHOSPHOPROTEIN phosphatases; ALLOSTERIC regulation
- Publication
Journal of Clinical Investigation, 2019, Vol 129, Issue 12, p5468
- ISSN
0021-9738
- Publication type
journal article
- DOI
10.1172/JCI130520