Pasupuleti, Santhosh KumarChao, KarenRamdas, BaskarKanumuri, RahulPalam, Lakshmi ReddyLiu, ShengWan, JunAnnesley, ColleenLoh, Mignon L.Stieglitz, ElliotBurke, Michael J.Kapur, Reuben2024-07-112024-07-112023Pasupuleti SK, Chao K, Ramdas B, et al. Potential clinical use of azacitidine and MEK inhibitor combination therapy in PTPN11-mutated juvenile myelomonocytic leukemia. Mol Ther. 2023;31(4):986-1001. doi:10.1016/j.ymthe.2023.01.030https://hdl.handle.net/1805/42118Juvenile myelomonocytic leukemia (JMML) is a rare myeloproliferative neoplasm of childhood. The molecular hallmark of JMML is hyperactivation of the Ras/MAPK pathway with the most common cause being mutations in the gene PTPN11, encoding the protein tyrosine phosphatase SHP2. Current strategies for treating JMML include using the hypomethylating agent, 5-azacitidine (5-Aza) or MEK inhibitors trametinib and PD0325901 (PD-901), but none of these are curative as monotherapy. Utilizing an Shp2E76K/+ murine model of JMML, we show that the combination of 5-Aza and PD-901 modulates several hematologic abnormalities often seen in JMML patients, in part by reducing the burden of leukemic hematopoietic stem and progenitor cells (HSC/Ps). The reduced JMML features in drug-treated mice were associated with a decrease in p-MEK and p-ERK levels in Shp2E76K/+ mice treated with the combination of 5-Aza and PD-901. RNA-sequencing analysis revealed a reduction in several RAS and MAPK signaling-related genes. Additionally, a decrease in the expression of genes associated with inflammation and myeloid leukemia was also observed in Shp2E76K/+ mice treated with the combination of the two drugs. Finally, we report two patients with JMML and PTPN11 mutations treated with 5-Aza, trametinib, and chemotherapy who experienced a clinical response because of the combination treatment.en-USPublisher PolicyMEK inhibitorPD-901Trametinib5-AzacitidineArticle