Oncotarget

Priority Research Papers:

Pharmacologic inhibition of PI3K p110δ in mutant Shp2E76K-expressing mice

Lisa Deng, Elizabeth L. Virts, Reuben Kapur and Rebecca J. Chan _

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Oncotarget. 2017; 8:84776-84781. https://doi.org/10.18632/oncotarget.21455

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Abstract

Lisa Deng1,2, Elizabeth L. Virts1,4, Reuben Kapur1,2,3,4 and Rebecca J. Chan1,2,4

1 Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, USA

2 Department of Medical & Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA

3 Department of Biochemistry & Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, USA

4 Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN, USA

Correspondence to:

Rebecca J. Chan, email:

Keywords: JMML, Shp2, PI3K p110δ, mouse model, in vivo

Abbreviations: JMML: juvenile myelomonocytic leukemia; GM-CSF: granulocyte macrophage colony-stimulating factor; GOF: gain-of-function; PI3K: phosphatidyl inositide-3 kinase; LDMNC: low-density mononuclear cell

Received: July 27, 2017 Accepted: September 08, 2017 Published: October 03, 2017

Abstract

Juvenile myelomonocytic leukemia is a childhood malignancy that lacks effective chemotherapies and thus has poor patient outcomes. PI3K p110δ has been found to promote hyperproliferation of cells expressing mutant Shp2. In this study, we tested the efficacy of a PI3Kδ inhibitor in mice expressing the Shp2 gain-of-function mutation, E76K. We found that in vivo treatment of mice led to significantly decreased splenomegaly, reduced frequency of bone marrow progenitor cells, and increased terminally differentiated peripheral blood myeloid cells. The survival of drug-treated mice was significantly prolonged compared to vehicle-treated controls, although mice from both groups ultimately succumbed to a similar myeloid cell expansion. PI3Kδ inhibitors are currently used to treat patients with relapsed lymphoid malignancies, such as chronic lymphocytic leukemia. The current findings provide evidence for using PI3Kδ inhibitors as a treatment strategy for JMML and potentially other myeloid diseases.


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