Targeting Stem-Cell Dependent Drug Resistance in Human MCL

描述（由申请人提供）：套细胞淋巴瘤（MCL）是一种致命的淋巴恶性肿瘤，起源于假定的B细胞。先前对MCL和其他淋巴瘤的研究揭示了具有干细胞样特征的肿瘤细胞的存在，尽管这些细胞类型的确切身份和分子特性几十年来一直不清楚。我们的研究小组使用了针对B细胞表面蛋白的单克隆抗体、新鲜分离的患者样本和小鼠有限稀释法， 表征来自多个MCL的干细胞样肿瘤细胞。MCL起始细胞（MCL-IC）的基因表达谱分析揭示，与大量肿瘤细胞相比，MCL-IC上调NF-κ B相关的信号传导组分和CXCR 4介导的动员途径。在这项提案中，我们将研究这些分子途径是如何相互联系，赋予生长，生存和耐药性的MCL-IC。在Aim 1中，我们将描述MCL耐药的分子机制，并将这些特征与干细胞样功能联系起来。我们假设干细胞样MCL细胞利用TG 2和NF-κ B信号传导来补偿由于缺乏CD 19表达而导致的B细胞受体介导的生长和存活减少，如在霍奇金淋巴瘤中所报道的。在Aim 2中，我们将通过抑制自噬来靶向耐药MCL细胞。我们发现硼替佐米治疗诱导MCL细胞中的自噬，有助于MCL细胞的存活。此外，TG 2/NF-kB通路在自噬中也发挥重要作用。我们假设硼替佐米耐药MCL细胞利用自噬作为IkBa降解的替代途径，这反过来又通过NF-kB激活增强了它们的存活。在Aim 3中，我们将通过抑制MCL细胞向骨髓的动员来增强MCL细胞的硼替佐米敏感性。我们已经证明MCL-IC响应于在骨髓微环境中表达的CXCL 12而迁移，并且针对CXCL 12的主要受体CXCR 4的中和抗体抑制它们的动员。我们假设MCL细胞上的CXCR 4信号介导与骨髓基质细胞的相互作用，并且破坏这些相互作用将使MCL细胞对硼替佐米敏感。鉴于某些癌症中的恶性干细胞具有高度耐药性，并在药物治疗后产生新的肿瘤，靶向MCL中干细胞中选择性表达的途径可能最终改善MCL患者的生存率。

DESCRIPTION (provided by applicant): Mantle cell lymphomas (MCLs) are deadly lymphoid malignancies that arise from presumptive B cells of origin. Prior studies of MCL and other lymphomas revealed the presence of tumor cells with stem-like characteristics, although the exact identities and molecular properties of these cell types have remained obscure for decades. Our group has used monoclonal antibodies directed against B cell surface proteins, freshly isolated patient samples, and limiting dilution assays in mice to prospectively isolate and characterize stem-like tumor cells from multiple MCL. Gene expression profiling analyses of MCL initiating cells (MCL-ICs) revealed that MCL- ICs up-regulate NF-kB related signaling components and CXCR4-mediated mobilization pathways compared to the bulk tumor cells. In this proposal we will investigate how these molecular pathways are interconnected to confer growth, survival and drug resistant properties to MCL-ICs. In Aim1 we will delineate molecular mechanisms of MCL drug resistance and link these features to stem-like functions. We hypothesize that stem-like MCL cells utilize TG2 and NF-kB signaling to compensate for diminished B cell receptor-mediated growth and survival due to lack of CD19 expression, as has been reported in Hodgkin's Lymphomas. In Aim2 we will target drug resistant MCL cells by inhibiting autophagy. We discovered that bortezomib treatment induces autophagy in MCL cells, contributing to survival of the MCL cells. In addition, TG2/NF-kB pathway is reported to play important functions for autophagy. We hypothesize that bortezomib resistant MCL cells utilize autophagy as an alternative route for IkBa degradation, which in turn enhances their survival via NF-kB activation. In Aim3 we will enhance bortezomib sensitivity of MCL cells by inhibiting their mobilization to the bone marrow. We have demonstrated that MCL-ICs migrate in response to CXCL12 which is expressed in the bone marrow microenvironment, and neutralizing antibodies directed against the major receptor for CXCL12, CXCR4, inhibit their mobilization. We hypothesize that the CXCR4 signaling on MCL cells mediates interactions with bone marrow stromal cells and that disrupting these interactions will sensitize MCL cells to bortezomib. Given that malignant stem cells in some cancers are highly drug resistant and give rise to new tumors after drug therapies, targeting the pathways selectively expressed in stem cells in MCL may ultimately improve survival of MCL patients.