Potential clinical use of azacitidine and MEK inhibitor combination therapy in PTPN11-mutated juvenile myelomonocytic leukemia
Year: 2023
Type: article
Abstract: Juvenile 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 Shp2 E76K/+ 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 Shp2 E76K/+ 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 Shp2 E76K/+ 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.
Source: Molecular Therapy
Institutions: Indiana University Indianapolis, Indiana University School of Medicine, Lucile Packard Children's Hospital, Medical College of Wisconsin, Stanford University, Seattle Children's Hospital, University of California, San Francisco, UCSF Helen Diller Family Comprehensive Cancer Center, Indiana University – Purdue University Indianapolis
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $3,900
Awards: Targeting Novel Pathways in JMML, Role of Shp2 in FLT3-ITD induced leukemogenesis, Hyperglycemia mediated myeloproliferative disease, Role of p21 activated kinase in Leukemogenesis, Developmental and Hyperactive Ras Tumor (DHART) SPORE, Implementation of an interventional, risk-adapted clinical trial for children with newly diagnosed juvenile myelomonocytic leukemia., Hematopoietic stem and progenitor cell regulation for enhanced clinical efficacy, Autophagy, Inflammation and Metabolism (AIM) in Disease Center - Phase 2.
OpenAlex ID: W4319072544