RNA seq analysis of MEK inhibitor in combination with 5-azacitidine treated Shp2E76K/+ driven JMML mice

Juvenile myelomonocytic leukemia (JMML) is a rare myelodysplastic and myeloproliferative neoplasm of childhood. Excessive proliferation of monocytes into the liver, spleen, lungs, and skin is frequently observed at presentation. Hematopoietic stem cell transplantation (HSCT) is the only curative therapy with a probability of event-free survival at 5-years of approximately 50%. The molecular hallmark of JMML is hyperactivation of the Ras/MAPK signaling pathway with the most common cause being mutations in the gene PTPN11, encoding the protein tyrosine phosphatase SHP2. Current therapeutic strategies in JMML include using MEK inhibitors such as trametinib and PD0325901 (PD-901) or the hypomethylating agent, 5-azactidine, but none of these are curative as monotherapy. In this study, utilizing a gain of function (GOF) Shp2E76K/+ murine model of JMML, we showed that the combination of PD-901 and 5-azacitidine reduced leukocytosis, monocytosis, and splenomegaly and reversed thrombocytopenia. Importantly, this drug combination significantly reduced leukemic hematopoietic stem and progenitor cells (HSC/Ps) in the Shp2E76K/+ mice.