The role of MALT1 in the molecular pathogenesis of mantle cell lymphoma

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Mantle cell lymphoma (MCL) accounts for approximately 8-10% of all malignant lymphoma cases and is characterized by adverse prognosis with a median overall survival of only three to five years. To improve therapeutic strategies and subsequently outcome of MCL patients, a significantly better understanding of MCL biology is critically warranted. The hallmark genetic aberration, which is detectable in more than 90% of MCL cases, is the chromosomal translocation t(11;14) (q13;q32) that juxtaposes the CCND1 gene to the immunoglobulin heavy chain locus, leading to deregulation and overexpression of the cell cycle regulator cyclin D1. Additional molecular aberrations are required for transformation and MCL lymphomagenesis. However, the functional role of these additional genetic abnormalities that significantly contribute to the molecular pathogenesis of MCL remain largely unknown. Previous work from our group has shown that constitutive activation of B-cell receptor (BCR) signaling and downstream activation of the oncogenic NF-kB pathway plays an important role in the biology of MCL. Preliminary data indicated that the paracaspase MALT1 is constitutively activated by BCR signaling and might be involved in MCL lymphomagenesis. Within the proposed project, we aim to decipher the role of MALT1 in the molecular pathogenesis of MCL. To this end, we will investigate if these lymphomas are addicted to MALT1 signaling. We will analyze, if MALT1 knockdown is toxic to MCL models. Subsequently, we will investigate the gene expression networks controlled by MALT1 by performing gene expression profiling. These results will be further validated in primary MCL patient samples to ensure that our data reflect the in vivo disease. Finally, we will investigate if pharmacologic MALT1 inhibition alone or in combination with selective BTK, PI3K, and BCL-2 small molecule inhibitors might represent a novel and promising strategy for future therapies of MCL patients. In summary, the proposed project will lead to a significantly better understanding of MCL biology and MALT1 signaling in MCL and might identify MALT1 as novel molecular target that can be attacked therapeutically in future studies to improve prognosis of affected patients.