Pharmacologic Inhibition of PI3Kδ Prolongs Survival of Mutant Shp2E76K-Expressing Mice

Juvenile myelomonocytic leukemia (JMML) is an aggressive overproduction of cells in the myeloid lineage, characterized by hypersensitivity to granulocyte macrophage colony-stimulating factor (GM-CSF). There is a clear need for improved chemotherapies, as the current treatments are ineffective. The most commonly mutated gene in JMML patients is PTPN11, which encodes the protein tyrosine phosphatase Shp2. One of the downstream targets of Shp2 is phosphoinositide 3-kinase (PI3K), and we have previously focused on the hematopoietic-specific catalytic subunit p110δ (PI3Kδ). The PI3Kδ inhibitor idelalisib is FDA-approved for patients with B cell malignancies. However, the effectiveness of PI3Kδ inhibition in JMML and other myeloid malignancies has not been studied. Therefore, following our previous work in vitro which demonstrated reduced proliferation of GOF Shp2-expressing murine cells and primary JMML cells (Goodwin et. al, Blood 2014), we assessed the effect of PI3Kδ inhibition on GOF Shp2-expressing mice in vivo as the next step in exploring PI3Kδ inhibition as a potential treatment in JMML.