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

套细胞淋巴瘤（MCL）约占所有恶性淋巴瘤病例的8-10%，其特点是预后不良，中位总生存期仅为3 - 5年。为了改善MCL患者的治疗策略和随后的结果，对MCL生物学的更好理解是至关重要的。在超过90%的MCL病例中可检测到的标志性遗传畸变是染色体易位t(11;14) (q13;q32)，它将CCND1基因与免疫球蛋白重链位点并置于一起，导致细胞周期调节因子cyclin D1的失调和过度表达。转化和MCL淋巴瘤形成需要额外的分子畸变。然而，这些额外的遗传异常在MCL分子发病机制中的功能作用在很大程度上仍然未知。本小组之前的工作表明，b细胞受体（BCR）信号的组成性激活和下游致癌NF-kB通路的激活在MCL的生物学中起着重要作用。初步数据表明，副aspase MALT1被BCR信号激活，可能参与MCL淋巴瘤的发生。在这个项目中，我们的目标是破译MALT1在MCL的分子发病机制中的作用。为此，我们将研究这些淋巴瘤是否依赖于MALT1信号。我们将分析MALT1敲低是否对MCL模型有毒。随后，我们将通过执行基因表达谱来研究由MALT1控制的基因表达网络。这些结果将在原发性MCL患者样本中进一步验证，以确保我们的数据反映体内疾病。最后，我们将研究是否单独或联合选择性BTK、PI3K和BCL-2小分子抑制剂的药理学MALT1抑制可能代表一种新的和有前途的策略，用于未来治疗MCL患者。综上所述，该项目将有助于更好地了解MCL生物学和MCL中的MALT1信号，并可能在未来的研究中发现MALT1作为新的分子靶点，可以通过治疗来改善患者的预后。

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.