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

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

Research output: Contribution to journalReview article

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.

Original languageEnglish (US)
Pages (from-to)5468-5473
Number of pages6
JournalJournal of Clinical Investigation
Volume129
Issue number12
DOIs
StatePublished - Dec 2 2019

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Genetic Models
Epigenomics
Acute Myeloid Leukemia
Mutation
Cytokine Receptors
Protein Tyrosine Phosphatases
Receptor Protein-Tyrosine Kinases
DNA Methylation
Karyotype
Cell Differentiation
Down-Regulation
Cell Proliferation
Gene Expression
Growth
SHP099
Therapeutics

ASJC Scopus subject areas

  • Medicine(all)

Cite this

SHP2 inhibition reduces leukemogenesis in models of combined genetic and epigenetic mutations. / Pandey, Ruchi; Ramdas, Baskar; Wan, Changlin; Sandusky, George; Mohseni, Morvarid; Zhang, Chi; Kapur, Reuben.

In: Journal of Clinical Investigation, Vol. 129, No. 12, 02.12.2019, p. 5468-5473.

Research output: Contribution to journalReview article

Pandey, Ruchi ; Ramdas, Baskar ; Wan, Changlin ; Sandusky, George ; Mohseni, Morvarid ; Zhang, Chi ; Kapur, Reuben. / SHP2 inhibition reduces leukemogenesis in models of combined genetic and epigenetic mutations. In: Journal of Clinical Investigation. 2019 ; Vol. 129, No. 12. pp. 5468-5473.
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AU - Zhang, Chi

AU - Kapur, Reuben

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