Identifying the oncogenic cooperation between IRF4 and MYD88l265p and their impact on the Tumor Microenvironment of Waldenstrom Macroglobulinemia
Patrizia Mondello
MD PhDMayo Clinic
Project Term: August 21, 2023 - August 20, 2025
Although many patients with IgM MGUS remain asymptomatic, some of them progress to Waldenstrom Macroglobulinemia (WM) requiring treatment. Recently, we have found that the hereditable alteration of IRF4 gene increases the risk to develop WM, however little is known on the molecular mechanisms responsible for this feature. In this project, we aim to elucidate the role of the germline alteration of IRF4 in promoting WM through oncogenic cooperation with MYD88 and dysregulated immune microenvironment, ultimately paving the way for novel precision therapies for this patient population.
Although many patients with IgM MGUS remain asymptomatic, some of them progress to Waldenstrom Macroglobulinemia (WM) requiring treatment. Recently, we have found that thehereditable alteration of IRF4 gene increases the risk to develop WM. However, a better understanding of the mechanism by which IRF4 promotes disease is needed. This information is critical to identifying novel and more effective therapies for WM.We propose to define the oncogenic cooperation between IRF4 and MYD88l265p, the hallmark mutation of WM, using cutting-edge technology including single cell sequencing and mass cytometry. We will leverage genetically engineered cell lines, transgenic mice and one of the largest cohorts of WM tumors with the corresponding germline, clinical and outcome data which will be used for analysis. This work has the potential to directly impact clinical practice by revealing a novel predictive biomarker of disease in MGUS patients and critical targetable vulnerabilities for more effective therapies in WM.