Role of SLAMF7 in Racial Disparities in Myeloma

项目摘要 我们的长期目标是改善所有多发性骨髓瘤（MM）患者的护理和结局，特别是 非裔美国人（AA）患者，以减少种族差异。MM表现出最显著的种族差异之一， AA和白色人之间。MM的发病率是AA的2-3倍，发生在更早的年龄 人士我们发现伴有t（11;14）易位骨髓瘤的AA患者的预后差于白色患者 即使在调整了合并症、疾病分期、治疗时间和血液使用后， 骨髓移植等。这种种族差异的机制尚不清楚。我们最近发现MM 来自AA患者的细胞具有较高的信号淋巴细胞活化分子家族成员表达， 7（SLAMF 7）的抑制作用，并且对SLAMF 7抗体交联的抑制作用更敏感。的目的 一项提案是确定埃罗妥珠单抗（FDA批准的人源化SLAMF 7单克隆抗体）的作用， AA和白色t（11;14）MM患者中SLAMF 7的差异及其机制 AA和白色t（11;14）MM患者之间的表达。我们的中心假设是埃罗妥珠单抗是 由于SLAMF 7的高表达，在患有t（11;14）MM的AA患者中特别有效。此外，本发明还 我们假设SLAMF 7启动子-742位点的A>G单核苷酸多态性（SNP）影响Blimp-1基因。 1-SLAMF 7基因的转录，并导致SLAMF 7表达的差异AA 患者和白色患者的t（11;14）MM。 了解埃罗妥珠单抗在患有t（11;14）MM的AA患者中的有效性以及该SNP的影响， 我们将能够开发更有效的治疗方案和生物标志物，以减少种族差异。我们 有两个具体目标。目的1是确定患有t（11;14）骨髓瘤的AA患者的临床结局， t（11;14）骨髓瘤白色患者对基于依洛珠单抗的治疗有应答。一项回顾性队列研究 将结合患者特征和社会经济决定因素， t（11;14）骨髓瘤AA患者与t（11;14）骨髓瘤白色患者的缓解和结局 用基于依洛珠单抗的方案治疗。将使用星星PCORnet数据集市， 将提取并分析总计257例t（11;14）MM患者。目的二是确定其作用机制 在患有t（11;14）MM的AA患者和白色患者之间SLAMF 7表达的差异的基础 染色质免疫沉淀试验，pGL-3荧光素酶报告系统，定点 诱变和四引物扩增抗性突变系统-PCR。我们的研究是 创新，因为它采用了新技术，代表了一种新的实质性的出发点， 这是从现状中取得的重大进步。我们的研究不仅将从根本上推进我们对种族歧视的认识， 它不仅对MM患者的治疗和结局有积极的转化影响， 对戒酒协会的人有不良影响

Project Summary Our long-term goal is to improve the care and outcomes of all patients with multiple myeloma (MM), particularly African American (AA) patients to reduce racial disparity. MM exhibits one of the most striking racial disparities between AA and White persons. MM has a 2-3 fold higher incidence and occurs at much earlier age in AA persons. We found that the outcomes of AA patients with translocation t(11;14) myeloma were inferior to White patients even after adjusted for comorbidities, disease stage, the length of treatment, and the use of blood and bone marrow transplantation, etc. The mechanism for this racial disparity is unclear. We recently found that MM cells from AA patients had a higher expression of the signaling lymphocyte activation molecule family member 7 (SLAMF7) and were more sensitive to the inhibition by SLAMF7 antibody crosslinking. The objective of this proposal is to determine the effects of elotuzumab (an FDA approved, humanized SLAMF7 monoclonal antibody) in AA and White patients with t(11;14) MM and the mechanism underlying the differences in SLAMF7 expression between AA and White patients with t(11;14) MM. Our central hypothesis is that elotuzumab is particularly effective in AA patients with t(11;14) MM because of the higher expression of SLAMF7. Additionally, we hypothesized that A>G single nucleotide polymorphism (SNP) at -742 of SLAMF7 promoter affects Blimp- 1- mediated SLAMF7 gene transcription and results in the differences in SLAMF7 expression between AA patients and White patients with t(11;14) MM. The rationale for the proposed study is that with greater understanding of the effectiveness of elotuzumab in AA patients with t(11;14) MM and the impact of this SNP, we will be able to develop a more effective treatment regimen and biomarkers to reduce racial disparities. We have two specific aims. Aim 1 is to determine the clinical outcomes of AA patients with t(11;14) myeloma and White patients with t(11;14) myeloma in response to elotuzumab-based treatment. A retrospective cohort study incorporating patient characteristics and social economic determinants will be performed to examine the response and outcomes between AA patients with t(11;14) myeloma and White patients with t(11;14) myeloma treated with elotuzumab-based regimens. STAR PCORnet datamart will be used and medical records from a total of 257 patients with t(11;14) MM will be extracted and analyzed. Aim 2 is to determine the mechanism underlying the differences in SLAMF7 expression between AA patients with t(11;14) MM and White patients with t(11;14) MM. Chromatin immunoprecipitation assay, pGL-3 luciferase reporter system, site directed mutagenesis, and tetra primer-amplification refractory mutation system-PCR will be performed. Our research is innovative, because it incorporates novel technology and represents a new and substantive departure and significant advance from the status quo. Our study will not only fundamentally advance our knowledge of racial disparitie, but also have a positive translational impact on the care and outcomes of patients with MM, a disease that affects AA population disproportionally.