role of BLyS/April in Normal and Malignant Plasma Cells

描述(由申请人提供)：我的实验室最近的研究发现了一种新的途径，促进了慢性B细胞恶性肿瘤的生存。我们证明了新发现的肿瘤坏死因子家族成员B淋巴细胞刺激物(BLyS)在白血病B细胞中以自分泌的方式表达，我们有初步的数据表明，类似的机制也可能在多发性骨髓瘤中起作用。BLyS对于维持B细胞的正常发育和动态平衡至关重要，与增殖诱导配体有显著的同源性(APRIL)。APRIL可刺激肿瘤细胞生长和原代淋巴细胞的增殖，在多种人类癌症中都有表达。BLyS和APRIL的受体有三种：B细胞成熟抗原(BCMA)、跨膜激活因子和CAML相互作用因子(TACI)和BAFF-R。BLyS与所有三种受体结合，而APRIL仅与TACI和BCMA结合。目前，每个受体在正常或恶性B细胞生物学中的确切作用，特别是终末分化的浆细胞，仍不清楚。我们有令人兴奋的初步证据表明，这些受体在骨髓瘤细胞中以不同的方式表达；外源性BLyS和APRIL促进骨髓瘤细胞的生长和提高细胞存活率；自分泌BLyS可能由骨髓瘤细胞表达。此外，初步的基因图谱实验表明，这两个分子都刺激了各种基因的诱导，包括一些先前与B细胞和其他细胞类型的分化有关的转录因子。鉴于BLyS对正常B细胞的维持和存活的显著影响以及我们自己的初步数据，本研究的中心假设是BLyS/APRIL-TACI/BCMA/BAFF-R配体-受体系统可能参与了多发性骨髓瘤的发病和维持。我们的核心假设有两个独立但高度集成的组成部分。首先，我们假设骨髓瘤细胞BCMA、TACI和/或BAFF-R的表达对肿瘤细胞的生存至关重要，可能反映了对正常浆细胞生存也至关重要的受体-配体系统的利用。此外，我们假设这三种受体既具有独特的属性，又具有冗余的属性，这可能通过受体表达的精确模式和/或水平来揭示。其次，我们假设骨髓瘤细胞中自分泌BLyS通路的激活是进一步利用该生存通路在恶性浆细胞中的新机制。我们提出了三个具体的目标：1)阐明BlyS/APRIL对正常和恶性浆细胞生存和生长的影响；2)研究BLyS/APRIL激活在恶性浆细胞中的下游信号和遗传后果；3)明确非典型骨髓瘤细胞表达BLyS的机制(S)。这种性质的研究有可能提出治疗这种疾病的新机会，并为这一新颖而有趣的分子家族在完全分化的B细胞中所扮演的角色提供基本的见解。

DESCRIPTION (provided by applicant): Recent studies in my laboratory have identified a novel pathway promoting enhanced survival of chronic B cell malignancies. We demonstrated that B lymphocyte stimulator (BLyS), a newly identified tumor necrosis factor (TNF) family member, was expressed in an autocrine manner in leukemic B cells and we have preliminary data that a similar mechanism may also be operative in multiple myeloma. BLyS is critical for maintenance of normal B cell development and homeostasis and shares significant homology with a proliferation-inducing ligand (APRIL). APRIL stimulates tumor cell growth as well as proliferation of primary lymphocytes and is expressed by a variety of human cancers. Three receptors for BLyS and APRIL have been identified: B cell maturation antigen (BCMA), transmembrane activator and CAML interactor (TACI), and BAFF-R. Whereas BLyS binds to all three receptors, APRIL only binds to TACI and BCMA. Currently, the precise role that each receptor plays in normal or malignant B cell biology, particularly terminally differentiated plasma cells, remains unknown. We have exciting preliminary evidence that these receptors are expressed in a heterogeneous fashion in myeloma cells; that exogenous BLyS and APRIL augment myeloma cell growth and enhance cell survival; and that autocrine BLyS may be expressed by myeloma cells. Furthermore, preliminary gene profiling experiments suggest that both of these molecules stimulate the induction of a variety of genes, including a number of transcription factors previously linked to differentiation in B cells as well as other cell types. Because of the striking effects of BLyS on normal B cell maintenance and survival and our own preliminary data, the central hypothesis of this proposal is that the BLyS/APRIL-TACI/BCMA/BAFF-R ligand-receptor system may be involved in the pathogenesis and maintenance of multiple myeloma. Our central hypothesis has two separate, but highly integrated components. First, we hypothesize that myeloma cell expression of BCMA, TACI, and/or BAFF-R is critical to tumor cell survival and may reflect exploitation of a receptor-ligand system that is also critical for normal plasma cell survival. Moreover, we hypothesize that these three receptors possess both unique and redundant properties, which may be revealed by the precise pattern and/or level of receptor expression. Second, we hypothesize that activation of an autocrine BLyS pathway in myeloma cells is a novel mechanism by which this survival pathway is further exploited in malignant plasma cells. We propose three specific aims: 1) elucidate the impact of BLyS/APRIL on normal and malignant plasma cell survival and growth; 2) characterize the down-stream signaling and genetic consequences of BLyS/APRIL activation in malignant plasma cells; and 3) define the mechanism(s) underlying atypical myeloma cell expression of BLyS. Studies of this nature have the potential to suggest new opportunities to treat this disease as well as provide basic insight into the role of this novel and intriguing family of molecules in fully differentiated B lineage cells.