Identifying the angiogenic receptor expression in mantle cell lymphoma patients and murine models.

Mantle Cell Lymphoma (MCL) is an aggressive B-cell non-Hodgkin lymphoma, with frequent relapses and shorter responses with every subsequent treatment. MCL depends on growth factors and cytokines derived from microenvironmental cells for its growth and can alter the immune system to evade recognition and subsequent elimination. The soluble factors secreted by MCL can contribute to endothelial differentiation, lymphangiogenesis, and clonal selection under hypoxic conditions, thereby evading the DNA damage response. Targeting the tumor microenvironment and angiogenesis is an active area of research and development, as the angiogenic gene signatures in MCL remain poorly understood. To address this knowledge gap, we performed transcriptomic analyses of MCL patient cohorts and identified 10 key angiogenic genes upregulated in MCL. We focused on four receptors (FGFR1, VEGFR1, VEGFR2, and PDGFRB) that have receptor tyrosine kinase activity and are localized to the plasma membranes of MCL cells. These receptors were assessed for therapeutic targeting potential in four independent preclinical models, including patient-derived xenografts, cell-derived xenografts, bone marrow-derived xenografts, and a genetically engineered murine model of MCL. Our work establishes that simultaneous targeting of multiple kinases, such as FGFR1 and VEGFR2, is a promising therapeutic strategy for patients with MCL.