High expression of endoplasmic reticulum chaperone grp94 is a novel molecular hallmark of malignant plasma cells in multiple myeloma.
High expression of endoplasmic reticulum chaperone grp94 is a novel molecular hallmark of malignant plasma cells in multiple myeloma.
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DOI：
10.1186/s13045-015-0177-6
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发表时间：
2015-06-25
影响因子：
28.5
通讯作者：
Liu B
中科院分区：
文献类型：
--
作者：
Chhabra S;Jain S;Wallace C;Hong F;Liu B
多发性骨髓瘤（MM）是一种血液恶性肿瘤，其特征为异常骨髓浆细胞（BMPC）增殖和免疫球蛋白或轻链过度产生，伴有终末器官损伤证据，如骨损伤、贫血、高钙血症和肾功能不全。MM的发病机制与内质网（ER）中未折叠蛋白反应（UPR）失调密切相关。通过转基因表达主UPR转录因子XBP 1 s（X-box结合蛋白1的UPR特异性剪接变体）证明，小鼠中UPR的组成性激活导致骨髓瘤。grp 94（gp 96）是ER中的关键下游伴侣，其介导UPR作为分泌途径中蛋白质质量控制机制的一部分。我们最近的研究表明，浆细胞的持久性以及骨髓瘤在XBP 1 s转基因小鼠的发展是严重依赖于grp 94。然而，grp 94在人类MM的起始和进展中的作用仍然未知。采用流式细胞术、实时荧光定量PCR和Western blot分析方法检测BMPC中grp 94的表达水平。我们比较了一系列患者的BMPC中grp 94的表达水平，包括MM、意义不明的单克隆丙种球蛋白病（MGUS）、闷烧MM（SMM）以及非浆细胞疾病（NPC）。我们发现grp 94在MM患者的恶性浆细胞中高表达，而在MGUS/SMM和NPC患者的BMPC中不表达。grp 94表达水平与CD 138表达水平显著相关。我们还发现来自国际分期系统（ISS）III期MM患者的BMPC中grp 94表达水平高于ISS I/II期MM患者。grp 94在MM的BMPC中高度表达，这与该疾病的晚期相关。我们的数据表明grp 94是一种新的诊断和预后生物标志物。它还将grp 94定位为MM的有希望的治疗靶点。
Multiple myeloma (MM) is a hematologic malignancy that is characterized by the proliferation of abnormal bone marrow plasma cells (BMPC) and overproduction of immunoglobulin or light chains with evidence of end-organ damage such as bone damage, anemia, hypercalcemia, and renal dysfunction. The pathogenesis of MM is closely linked to dysregulated unfolded protein response (UPR) in the endoplasmic reticulum (ER). Constitutive activation of UPR in mice, as demonstrated by transgenic expression of a master UPR transcription factor XBP1s (a UPR-specific splice variant of X-box binding protein 1), causes myeloma. grp94 (gp96) is a key downstream chaperone in the ER that mediates the UPR as a part of the protein quality control mechanism in the secretory pathway. Our recent study has shown that the persistence of plasma cells as well as the development of myeloma in XBP1s-transgenic mice is critically dependent on grp94. However, the role of grp94 in the initiation and progression of human MM is still unknown. The expression level of grp94 in BMPCs was measured by flow cytometry, real-time RT-PCR, and Western blot analysis. We compared the expression levels of grp94 in BMPCs in a spectrum of patients including MM, monoclonal gammopathy of undetermined significance (MGUS), smoldering MM (SMM), as well as non-plasma cell disorders (NPC). We found that grp94 was highly expressed in malignant plasma cells in patients with MM, but not in BMPCs in patients with MGUS/SMM and NPC. The expression level of grp94 correlated significantly with CD138 expression level. We also found that the grp94 expression level in BMPCs from International Staging System (ISS) stage III MM patients is higher than those in ISS stage I/II MM patients. grp94 is highly expressed in BMPCs in MM, which correlates with the advanced stage of this disease. Our data demonstrated that grp94 is a novel diagnostic and prognostic biomarker. It also positioned grp94 as a promising therapeutic target for MM.
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影响因子：
11.5
作者：
Ashihara, Eishi;Kawata, Eri;Maekawa, Taira
通讯作者：
Maekawa, Taira
影响因子：
11.4
作者：
通讯作者：
--
通过结构优化鉴定出一种有前景的 PI3K 抑制剂用于治疗多发性骨髓瘤
影响因子：
28.5
作者：
Han K;Xu X;Chen G;Zeng Y;Zhu J;Du X;Zhang Z;Cao B;Liu Z;Mao X
通讯作者：
Mao X
DOI：
10.1073/pnas.0305855101
发表时间：
2004-04-20
影响因子：
11.1
作者：
Derksen, PWB;Tjin, E;Pals, ST
通讯作者：
Pals, ST
影响因子：
11.4
作者：
Avet-Loiseau, H.;Durie, B. G. M.;Cavo, M.;Attal, M.;Gutierrez, N.;Haessler, J.;Goldschmidt, H.;Hajek, R.;Lee, J. H.;Sezer, O.;Barlogie, B.;Crowley, J.;Fonseca, R.;Testoni, N.;Ross, F.;Rajkumar, S. V.;Sonneveld, P.;Lahuerta, J.;Moreau, P.;Morgan, G.
通讯作者：
Morgan, G.