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)患者的护理和预后，特别是 非裔美国人(AA)患者减少种族差异。MM展示了最显著的种族差异之一 在戒酒协会和白人之间。多发性骨髓瘤的发病率是再生障碍性贫血的2-3倍，并且发生在更早的年龄。 人。我们发现t(11；14)易位的再生障碍性贫血患者的预后不如白色 患者即使在调整了合并症、疾病阶段、治疗时间和血液使用情况后也是如此 骨髓移植等。造成这种种族差异的机制尚不清楚。我们最近发现MM 再生障碍性贫血患者细胞高表达信号淋巴细胞活化分子家族成员 7(SLAMF7)，对SLAMF7抗体的抑制更为敏感。这样做的目的是 建议确定elotuzumab(FDA批准的人源化SLAMF7单抗)的效果 T(11；14)MM的AA和White患者的SLAMF7差异及其机制 T(11；14)MM的AA和White患者之间的表达我们的中心假设是elotuzumab是 对于t(11；14)MM的再障患者尤其有效，因为SLAMF7的表达较高。另外， 我们推测SLAMF7启动子-742位的A&GT；G单核苷酸多态(SNP)会影响Blimp-Blimp。 1介导的SLAMF7基因转录及其导致再生障碍性贫血患者SLAMF7表达的差异 患者和患有t(11；14)MM的白人患者。拟议研究的基本原理是 了解elotuzumab治疗t(11；14)MM再生障碍性贫血患者的疗效及其SNP的影响， 我们将能够开发出更有效的治疗方案和生物标记物，以减少种族差异。我们 有两个明确的目标。目的1确定再生障碍性贫血合并t(11；14)骨髓瘤患者的临床结局。 患有t(11；14)骨髓瘤的白人患者对以elotuzumab为基础的治疗的反应。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进行检查 T(11；14)骨髓瘤AA和白人t(11；14)骨髓瘤患者的疗效和转归 使用以elotuzumab为基础的治疗方案。将使用STAR PCORnet Datamart，并从 共257例t(11；14)MM患者将被提取并分析。目标2是确定机制 T(11；14)MM再生障碍性贫血患者与白人患者SLAMF7表达的差异 T(11；14)MM染色质免疫沉淀法，PGL-3荧光素酶报告系统，定点 将进行诱变和四引物扩增难治突变系统-聚合酶链式反应。我们的研究是 创新，因为它融入了新的技术，代表着新的实质性的起点和 与现状相比有了很大的进步。我们的研究不仅将从根本上提高我们对种族问题的认识 不同，但对MM患者的护理和预后也有积极的转化影响 这会不成比例地影响再生障碍性贫血的人口。

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.