role of BLyS/April in Normal and Malignant Plasma Cells

描述（由申请人提供）：我实验室最近的研究已经确定了一种促进慢性B细胞恶性肿瘤生存率提高的新途径。我们证明，B淋巴细胞刺激因子（BLyS），一个新发现的肿瘤坏死因子（TNF）家族成员，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对于维持正常B细胞发育和稳态至关重要，并且与增殖诱导配体（APRIL）具有显著同源性。APRIL刺激肿瘤细胞生长以及原代淋巴细胞的增殖，并且由多种人类癌症表达。已经鉴定了BLyS和APRIL的三种受体：B细胞成熟抗原（BCMA）、跨膜激活剂和CAML相互作用物（TACI）和BAFF-R。而BLyS结合所有三种受体，APRIL仅结合TACI和BCMA。目前，每种受体在正常或恶性B细胞生物学，特别是终末分化的浆细胞中所起的确切作用仍然未知。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异质方式表达;外源性BLyS和APRIL增强骨髓瘤细胞生长并提高细胞存活率;自分泌BLyS可能由骨髓瘤细胞表达。此外，初步的基因分析实验表明，这两种分子都刺激诱导多种基因，包括许多先前与B细胞以及其他细胞类型分化相关的转录因子。由于BLyS对正常B细胞的维持和存活的显著作用以及我们自己的初步数据，该提议的中心假设是BLyS/APRIL-TACI/BCMA/BAFF-R配体-受体系统可能参与多发性骨髓瘤的发病和维持。我们的中心假设有两个独立但高度整合的组成部分。首先，我们假设骨髓瘤细胞表达BCMA、TACI和/或BAFF-R对肿瘤细胞存活至关重要，并可能反映了受体-配体系统的利用，该系统对正常浆细胞存活也至关重要。此外，我们假设这三种受体具有独特和冗余的特性，这可能是由受体表达的精确模式和/或水平揭示的。其次，我们假设骨髓瘤细胞中自分泌BLyS途径的激活是一种新机制，通过这种机制，这种生存途径在恶性浆细胞中被进一步利用。我们提出了三个具体目标：1）阐明BLyS/APRIL对正常和恶性浆细胞存活和生长的影响; 2）表征恶性浆细胞中BLyS/APRIL活化的下游信号传导和遗传后果;以及3）定义BLyS的非典型骨髓瘤细胞表达的潜在机制。这种性质的研究有可能提出治疗这种疾病的新机会，并提供对这种新的和有趣的分子家族在完全分化的B谱系细胞中的作用的基本见解。

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.