Expression of CD38 in myeloma bone niche: A rational basis for the use of anti-CD38 immunotherapy to inhibit osteoclast formation.
Expression of CD38 in myeloma bone niche: A rational basis for the use of anti-CD38 immunotherapy to inhibit osteoclast formation.
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DOI：
10.18632/oncotarget.17896
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发表时间：
2017-08-22
期刊：
影响因子：
--
通讯作者：
Giuliani N
中科院分区：
文献类型：
--
作者：
Costa F;Toscani D;Chillemi A;Quarona V;Bolzoni M;Marchica V;Vescovini R;Mancini C;Martella E;Campanini N;Schifano C;Bonomini S;Accardi F;Horenstein AL;Aversa F;Malavasi F;Giuliani N
已知多发性骨髓瘤（MM）细胞表达CD38，并且最近开发的人抗CD38单克隆抗体达雷妥尤单抗介导骨髓瘤杀伤。然而，MM骨龛内CD38和其他功能相关胞外酶的表达以及达雷妥尤单抗对骨细胞的潜在影响仍未知。本研究首先通过流式细胞术和免疫组化确定了MM和惰性单克隆丙种球蛋白病患者骨髓细胞CD38的表达。结果表明，只有浆细胞在骨龛内高水平表达CD 38。此外，流式细胞术分析显示，CD38也表达于单核细胞和早期破骨细胞祖细胞，而不表达于成骨细胞和成熟破骨细胞。事实上，CD38在体外破骨细胞生成过程中丢失。因此，我们发现达雷妥尤单抗与单核细胞上表达的CD38反应，其结合抑制MM患者骨髓总单核细胞的体外破骨细胞生成和骨吸收活性，靶向早期破骨细胞祖细胞。在纯化的CD14+细胞中未观察到抑制作用，表明达雷妥尤单抗具有间接抑制作用。有趣的是，全反式维甲酸处理增加了达雷妥尤单抗对破骨细胞形成的抑制作用。这些观察结果为使用基于抗CD 38抗体的方法治疗多发性骨髓瘤诱导的破骨细胞生成提供了依据。
It is known that multiple myeloma (MM) cells express CD38 and that a recently developed human anti-CD38 monoclonal antibody Daratumumab mediates myeloma killing. However, the expression of CD38 and other functionally related ectoenzymes within the MM bone niche and the potential effects of Daratumumab on bone cells are still unknown. This study firstly defines by flow cytometry and immunohistochemistry the expression of CD38 by bone marrow cells in a cohort of patients with MM and indolent monoclonal gammopathies. Results indicate that only plasma cells expressed CD38 at high level within the bone niche. In addition, the flow cytometry analysis shows that CD38 was also expressed by monocytes and early osteoclast progenitors but not by osteoblasts and mature osteoclasts. Indeed, CD38 was lost during in vitro osteoclastogenesis. Consistently, we found that Daratumumab reacted with CD38 expressed on monocytes and its binding inhibited in vitro osteoclastogenesis and bone resorption activity from bone marrow total mononuclear cells of MM patients, targeting early osteoclast progenitors. The inhibitory effect was not observed from purified CD14+ cells, suggesting an indirect inhibitory effect of Daratumumab. Interestingly, all-trans retinoic acid treatment increased the inhibitory effect of Daratumumab on osteoclast formation. These observations provide a rationale for the use of an anti-CD38 antibody-based approach as treatment for multiple myeloma-induced osteoclastogenesis.
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影响因子：
50.3
作者：
Becker A;Thakur BK;Weiss JM;Kim HS;Peinado H;Lyden D
通讯作者：
Lyden D
影响因子：
7.2
作者：
Horenstein AL;Chillemi A;Zaccarello G;Bruzzone S;Quarona V;Zito A;Serra S;Malavasi F
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影响因子：
4.8
作者：
Aarhus, R;Graeff, RM;Lee, HC
通讯作者：
Lee, HC
影响因子：
5.7
作者：
Chillemi, Antonella;Zaccarello, Gianluca;Malavasi, Fabio
通讯作者：
Malavasi, Fabio
DOI：
10.1111/nyas.12485
发表时间：
2015-01-01
期刊：
MARROW
影响因子：
--
作者：
Quarona, Valeria;Ferri, Valentina;Malavasi, Fabio
通讯作者：
Malavasi, Fabio