CD28-mediated Regulation of Multiple Myeloma Cell Proliferation and Survival

描述（由申请人提供）：多发性骨髓瘤（MM）是一种骨髓（BM）常驻浆细胞（PC）的肿瘤，占所有血液恶性肿瘤的20%，尽管有新的化疗药物仍然无法治愈。骨髓瘤细胞的生存严重依赖于与骨髓基质龛的相互作用，就像它们的正常对立物——骨髓常驻长寿命PC （LLPC）一样。越来越明显的是，这些相互作用在MM对化疗的耐药性中起主要作用，这是这种癌症治疗失败的主要原因。然而，尽管它们具有核心重要性，但参与这些相互作用的特定分子和细胞成分仍然缺乏特征。虽然其主要特征是作为参与T细胞活化和存活的原型T细胞共刺激受体，但CD28也在正常和恶性PC和骨髓瘤中表达，其过表达与预后不良、疾病进展和较短的生存期显著相关。在上一个资助周期中，我们已经在患者基因表达谱中表明，CD28过表达与疾病进展和预后不良的患者亚组相关，并且在MM细胞上激活CD28可以防止化疗诱导的死亡。我们现在已经发现，阻断CD28激活可导致MM细胞在体内和体外死亡，并使骨髓瘤对化疗敏感。此外，我们还观察到pc固有的CD28功能在维持正常BM LLPC的存活中也起着至关重要的作用。因此，CD28似乎调节正常PC生物学的基本方面，这些方面在骨髓瘤生物学中是保守的，因为它们在生存中起着重要作用。我们随后确定了CD28激活下游的Vav途径在BM LLPC中转导CD28的促生存信号。该通路上调转录调控因子BLIMP-1的表达，BLIMP-1是正常PC身份的“主调控因子”，但其在MM生物学中的作用在很大程度上尚未被探索。我们现在假设CD28Vav通路调节了维持PC身份所需的中心转录联系，并且这种身份对于MM的生存和化疗耐药性是必要的。本提案的总体目标是确定支持骨髓瘤细胞存活的CD28激活下游的信号通路和分子靶点。这种认识可能会导致MM，特别是化疗耐药疾病的新治疗靶点的确定和新治疗策略的发展。具体目标是：1)。定义CD28激活下游的信号通路，内在地调节骨髓瘤细胞的存活，2)。确定CD28Vav信号调控骨髓瘤细胞存活的分子靶点；3)。在体内测定阻断CD28激活的抗骨髓瘤效果。

DESCRIPTION (provided by applicant): Multiple myeloma (MM) is a neoplasm of bone marrow (BM) resident plasma cells (PC) that comprises 20% of all hematologic malignancies, and despite new chemotherapeutic agents remains incurable. Myeloma cells are critically dependent on interactions with BM stromal niches for their survival, just like their normal counterparts the BM-resident long-lived PC (LLPC). It is also becoming evident that these interactions play a major role in MM resistance to chemotherapy, the primary cause of treatment failure in this cancer. Despite their central importance however, the specific molecular and cellular components involved in these interactions remain poorly characterized. Although it is primarily characterized as the prototype T cell costimulatory receptor involved in T cell activatio and survival, CD28 is also expressed on normal and malignant PC - and in myeloma its overexpression correlates significantly with poor prognosis, disease progression and shorter survival. Over the last funding cycle, we have shown in patient gene expression profiles that CD28 overexpression is associated with disease progression and poor prognosis patient subgroups, and that activation of CD28 on MM cells protects against chemotherapy-induced death. We have now found that blocking CD28 activation leads to MM cell death in vitro and in vivo, and sensitizes the myeloma to chemotherapy. In addition, we have made the novel observation that PC-intrinsic CD28 function also plays an essential role in sustaining the survival of normal BM LLPC. Thus it appears that CD28 regulates fundamental aspects of normal PC biology that are conserved in myeloma biology due to their essential role in survival. We have subsequently determined that the Vav pathway downstream of CD28 activation transduces CD28's pro-survival signal in BM LLPC. This pathway upregulates expression of the transcriptional regulator BLIMP-1, the "master regulator" of normal PC identity - but whose role in MM biology has been largely unexplored. We now hypothesize that the CD28Vav pathway regulates a central transcriptional nexus that is required to maintain PC identity, and that this identity is necessary for MM survival and resistance to chemotherapy. The overall goal of this proposal is to define the signaling pathways and molecular targets downstream of CD28 activation that support myeloma cell survival. This understanding is likely to lead to the identification of new therapeutic targets and development of novel treatment strategies for MM, especially chemotherapy resistant disease. The Specific Aims are: 1). Define the signaling pathways downstream of CD28 activation that intrinsically regulate myeloma cell survival, 2). Define the molecular targets of CD28Vav signaling that regulate myeloma cell survival, and 3). Determine the anti-myeloma efficacy of blocking CD28 activation in vivo.