The role of lymphoid tissue SPARC in the pathogenesis and response to treatment of multiple myeloma.
The role of lymphoid tissue SPARC in the pathogenesis and response to treatment of multiple myeloma.
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DOI：
10.3389/fonc.2022.1009993
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发表时间：
2022
影响因子：
4.7
通讯作者：
Pitzalis, Costantino
中科院分区：
文献类型：
--
作者：
Aly, Nesreen Amer Ramadan;Rizk, Samia;Enein, Azza Aboul;El Desoukey, Nermeen;Zawam, Hamdy;Ahmed, Manzoor;El Shikh, Mohey Eldin;Pitzalis, Costantino
关键词：
尽管多发性骨髓瘤(MM)的治疗取得了重大进展，但这种疾病仍然无法治愈，其治愈仍然是临床上尚未满足的需求。MM的肿瘤转化始于次级淋巴组织(SLT)的生发中心(GCs)，B细胞在滤泡树突状细胞(FDCs)和T细胞信号的诱导下经历广泛的体细胞超突变。我们推测，富含半胱氨酸的酸性分泌蛋白(SPARC)在MM的起源(SLT)和目的地(BM)处由FDCs表达的一个常见的基质基序，在MM的发病机制中发挥了作用，在这里，我们试图探讨这一作用。57例多发性骨髓瘤患者的107例骨髓活检组织(在不同时间点采集)和13例对照样本一起评估了SPARC基因和蛋白的表达，并与扁桃体组织进行了比较。此外，在体外GC反应(GCR)中评估了分泌SPARC的FDCs对骨髓瘤促进基因的调节。SPARC基因在人原发(BM)和继发(扁桃体)淋巴组织中均有表达，且在BM中的表达显著高于BM。SPARC在骨髓和扁桃体裂解物中可检测到，并与FDC标记在这两个组织中共定位，体外刺激FDCs诱导的SPARC表达水平显著高于未刺激的对照组。此外，SPARC与MM患者的骨髓PC浸润、ISS分期和ECOG表现呈负相关，在体外向淋巴细胞中加入FDCs抑制了与PC恶性转化相关的几个癌基因的表达。FDC-SPARC可抑制多种骨髓生成基因的表达，并与PC的侵袭和MM的进展呈负相关。通过组合现有的MM药物、非MM药物的重新定位或新的药物发现来治疗诱导SPARC的表达，可以为更好地控制临床上重症和耐药的MM患者铺平道路。
Despite the significant progress in the treatment of multiple myeloma (MM), the disease remains untreatable and its cure is still an unmet clinical need. Neoplastic transformation in MM is initiated in the germinal centers (GCs) of secondary lymphoid tissue (SLT) where B cells experience extensive somatic hypermutation induced by follicular dendritic cells (FDCs) and T-cell signals. We reason that secreted protein acidic and rich in cysteine (SPARC), a common stromal motif expressed by FDCs at the origin (SLTs) and the destination (BM) of MM, plays a role in the pathogenesis of MM, and, here, we sought to investigate this role. There were 107 BM biopsies from 57 MM patients (taken at different time points) together with 13 control specimens assessed for SPARC gene and protein expression and compared with tonsillar tissues. In addition, regulation of myeloma-promoting genes by SPARC-secreting FDCs was assessed in in vitro GC reactions (GCRs). SPARC gene expression was confirmed in both human primary (BM) and secondary (tonsils) lymphoid tissues, and the expression was significantly higher in the BM. Sparc was detectable in the BM and tonsillar lysates, co-localized with the FDC markers in both tissues, and stimulation of FDCs in vitro induced significantly higher levels of SPARC expression than unstimulated controls. In addition, SPARC inversely correlated with BM PC infiltration, ISS staging, and ECOG performance of the MM patients, and in vitro addition of FDCs to lymphocytes inhibited the expression of several oncogenes associated with malignant transformation of PCs. FDC-SPARC inhibits several myelomagenic gene expression and inversely correlates with PC infiltration and MM progression. Therapeutic induction of SPARC expression through combinations of the current MM drugs, repositioning of non-MM drugs, or novel drug discovery could pave the way to better control MM in clinically severe and drug-resistant patients.
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影响因子：
3.7
作者：
Abdi J;Mutis T;Garssen J;Redegeld F
通讯作者：
Redegeld F
影响因子：
5.4
作者：
El Shikh, Mohey Eldin;El Sayed, Rania;Tew, John G.
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Tew, John G.
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Klein, B
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作者：
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Merlini, Giampaolo
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2
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Michal, Michal