Targeting Novel Inflammatory Signaling Pathways in Juvenile Myelomonocytic Leukemia
Juvenile Myelomonocytic Leukemia (JMML) is a rare and aggressive blood cancer mainly affecting young children. It is characterized by the presence of somatic PTPN11 mutations in approximately 35% of cases. Current treatments, like chemotherapy, are not very effective, and stem cell transplants are the only potential cure, but they only work for about half of patients, with relapse being the leading cause of death. Surprisingly, there are currently no FDA-approved medications for treating JMML. Chronic inflammation seems to be involved in JMML development. Certain immune cells called M2-Macrophages, which are elevated in JMML, play a role in immune suppression and cancer cell growth. We have found that certain proteins, PTX3 and IL-15, contribute to tumor growth, suppress cytotoxic T-cell activation and proliferation, leading to immunosuppression and leukemia relapse. With funds from this ALSF "A” Grant Award, we will test specific inhibitors such as anti-PTX3 inhibitor and anti-IL-15RA antibody, alongside established inhibitors such as MEK-inhibitor (PD-901) in PTPN11-mutant JMML mouse model, may rescue T-cell immune suppression and reverse the disease features of JMML.
Project Goal:
Over the course of the four-year ALSF "A” Grant Award, our primary goal is to elucidate the role of the immunotherapy including, PTX3/IL-15RA signaling axis along with MEK inhibition, in the development and treatment of juvenile myelomonocytic leukemia (JMML). JMML is a devastating blood cancer that predominantly affects young children, with limited successful treatment options, notably allogeneic hematopoietic stem cell transplantation (HSCT). Our overarching objective is to fill crucial knowledge gaps concerning the inflammatory processes driving JMML progression. Specifically, we aim to understand how dysregulated PTX3/IL15RA signaling contributes to the abnormal polarization of tumor-associated M2-macrophages within the leukemic microenvironment of JMML bone marrow. By leveraging cutting-edge techniques such as single-cell RNA sequencing and murine models of JMML, we aim to delineate the molecular pathways through which PTX3 and IL-15RA modulate macrophage polarization and promote immune evasion and leukemia relapse in JMML. Through comprehensive in vitro and in vivo experiments, we aim to validate PTX3/IL-15RA along with MEK inhibition as therapeutic targets for JMML and investigate the efficacy of specific inhibitors in rescuing T-cell immune suppression and reversing JMML disease features.
