血源播散的EMM是MM的特殊类型，生物学特征及临床表现与MM具有明显的异质性，预后极差。最新研究和项目组前期研究均发现热休克因子HSF1在EMM中表达明显增高，但其在EMM发病机制中的作用及其调控机制尚不清楚。新近研究发现m6A甲基化异常在肿瘤的侵袭和转移中起着重要作用，而且m6A甲基化修饰和热休克反应密切相关。课题组预实验发现EMM中m6A甲基化水平降低，去甲基化酶FTO表达上调，且FTO与HSF1的表达正相关。据此推测FTO可能通过m6A去甲基化修饰上调靶基因HSF1及相关蛋白的表达，促进EMM发生发展。本项目拟采用FTO表达/拮抗实验和MeRIP-seq结合临床资料的分析验证HSF1是否为FTO的靶基因，进而研究异常表达的FTO和HSF1对MM细胞增殖、迁移和侵袭的影响，并通过小鼠模型进行体内研究，最终确定FTO和HSF1在EMM发生中的作用，并探讨以FTO为靶点治疗EMM的可行性。

Extramedullary myeloma (EMM), defined by the presence of clonal plasma cells outside the bone marrow, has extraordinarily heterogeneous biological and clinical features and is associated with an adverse prognosis. Recent and our preliminary studies have shown the upregulation of heat shock transcription factor 1 (HSF1) in EMM, but little is known about its role and the mechanisms underlying the regulation. There is growing evidence that dysregulation of m6A RNA methylation plays an important role in tumor invasion and metastasis, and the m6A RNA modifications are involved in the heat shock response. Our preliminary data revealed reduced m6A RNA methylation and increased demethylases FTO expression, which is positively correlated to HSF1 expression in EMM. Therefore, we hypothesize that FTO may regulate HSF1 expression through m6A RNA methylation and promote extramedullary progression of multiple myeloma. Here we plan first to verify whether HSF1 is a target gene of FTO in EMM using MeRIP-seq (methylated RNA immunoprecipitation sequencing) analysis of FTO-overexpressed and FTO-knockdown MM cells, and then confirm the findings with our clinical data. Next we will investigate the impact of dysregulated FTO and HSF1 on MM cell proliferation, invasion and metastasis both in vitro and in vivo using a mouse model. The ultimate aim is to elucidate the role of FTO and HSF1 in EMM and to evaluate the potential of FTO as a novel therapeutic target for EMM.