New Investigator Research Grant Program

Juvenile Myelomonocytic Leukemia (JMML) is a rare and aggressive blood cancer primarily affecting young children. It is characterized by mutations in the PTPN11 gene, found in about 35% of cases. Current treatment options, including traditional chemotherapeutic agents, have limited efficacy, highlighting the urgent need for alternative therapeutic approaches. The cause of JMML remains unclear, but emerging evidence suggests chronic inflammation might play a role. Chronic inflammation is linked to many cancers, including leukemia. Within the JMML microenvironment, macrophages play a pivotal role, with tumor-associated macrophages promoting immune suppression and tumor progression. Preliminary data from both JMML patients and mouse models indicate elevated levels of M2 macrophages, along with increased expression of key inflammatory mediators, including pentraxin 3 (PTX3) and interleukin-15 (IL-15). Additionally, reduced percentages of T-cells with enhanced expression of T-cell exhaustion markers suggest immune suppression in JMML. We hypothesize that overexpression of PTX3 and IL-15RA in mutant macrophages induces MCP-1 secretion, leading to increased M2 macrophage polarization, tumor growth promotion, and T-cell immune suppression potentially driving JMML development and leukemia relapse. Targeting the PTX3/IL-15RA axis with specific inhibitors may offer a promising therapeutic strategy for JMML, potentially reversing immune suppression and improving patient outcomes.