New Multi-Drug Resistance Mechanism in Multiple Myeloma

多发性骨髓瘤(MM)是第二种最常见的血液系统恶性肿瘤，目前被认为 不治之症，中位生存期5-7年。新的药物，如蛋白酶体抑制剂，具有免疫调节作用 药物和单抗与更传统的药物相结合，可以实现更好的临床反应。 然而，对这些药物的耐药性的产生仍然是患者死亡的主要原因。还有一个 很大一部分新诊断的多发性骨髓瘤患者即使对这些新药物也是无效的，因此 没有从最近的治疗进展中受益。我们之前发现许多多发性骨髓瘤患者起源于 骨髓间充质基质细胞(BMSCs)是一种重要的MM肿瘤微环境细胞类型，可分泌 激活转录因子NF-κB并导致多发性骨髓瘤蛋白酶体抑制耐药的S因子 细胞。我们现在确定HAPLN1(透明质酸和蛋白多糖连接蛋白1)是一种负责的骨髓间充质干细胞分泌 在体外和体内也导致MM细胞产生这种耐药性的因素。RNA-SEQ与生物信息学分析 发现HAPLN1可诱导大规模转录改变，包括诱导一系列抗细胞凋亡 基因。相应地，HAPLN1也在体外引起MM细胞对多种其他药物的耐药性。HAPLN1病毒 MM BMSCs的表达高于正常BMSCs，HAPLN1的蛋白水解型通常是 在高度治疗难治性多发性骨髓瘤患者的骨髓血浆中检测到。因此，我们假设HAPLN1 是多发性骨髓瘤新的致癌因子和多药耐药诱导剂。这一假设将通过以下方式检验 确定HAPLN1在原代多发性骨髓瘤患者细胞和体内的病理作用(目标1)，阐明 HAPLN1介导MM耐药机制(AIM 2)及免疫靶向HAPLN1介导的药物 MM中的阻力(目标3)。总体而言，拟议的研究可能会将可溶性HAPLN1确定为一种新的 多发性骨髓瘤耐药及防治多药耐药的新靶点 MM中的问题

Multiple myeloma (MM) is the second most common hematologic malignancies and is currently considered incurable with a 5-7 year median survival. Newer drugs, such as the proteasome inhibitors, immunomodulatory drugs and monoclonal antibodies in combination with more traditional drugs enable better clinical responses. However, development of resistance to these drugs is still the major cause of patient demise. There is also a significant fraction of newly diagnosed MM patients who are refractory even to these newer drugs and thus have not benefited from the recent therapeutic advancements. We previously found that many MM patient-derived bone marrow mesenchymal stromal cells (BMSCs), a key MM tumor microenvironment cell type, secrete factor(s) capable of activating transcription factor NF-κB and causing proteasome inhibitor resistance in MM cells. We now identified HAPLN1 (hyaluronan and proteoglycan link protein 1) as a responsible BMSC secreted factor that also causes such drug resistance in MM cells in vitro and in vivo. RNA-seq and bioinformatic analyses revealed that HAPLN1 induces large-scale transcriptomic changes, including induction of a host of antiapoptotic genes. Accordingly, HAPLN1 also causes resistance to multiple other drugs in MM cells in vitro. HAPLN1 expression is higher in MM BMSCs relative to normal BMSCs, and proteolytic forms of HAPLN1 are often detected in bone marrow plasma from highly therapy refractory MM patients. Thus, we hypothesize that HAPLN1 is a new oncogenic factor and multi-drug resistance inducer in MM disease. This hypothesis will be tested by determining the pathologic role of HAPLN1 in primary MM patient cells and in vivo (Aim 1), elucidating the mechanism of HAPLN1-mediated drug resistance in MM (Aim 2), and immuno-targeting HAPLN1-mediated drug resistance in MM (Aim 3). Overall, the proposed study may identify soluble HAPLN1 as a novel marker for therapy resistance in MM, as well as a new therapeutic target to prevent or reduce the multi-drug resistance problem in MM.