CD28-mediated regulation of multiple myeloma cell proliferation and survival
CD28-mediated regulation of multiple myeloma cell proliferation and survival
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DOI：
10.1182/blood-2006-03-012542
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发表时间：
2007-06-01
期刊：
影响因子：
20.3
通讯作者：
Lee, Kelvin P.
中科院分区：
文献类型：
--
作者：
Bahlis, Nizar J.;King, Anne M.;Lee, Kelvin P.
虽然与骨髓基质细胞的相互作用对于多发性骨髓瘤（MM）细胞存活至关重要，但所涉及的特定分子和细胞元素在很大程度上是未知的，这在很大程度上是由于骨髓微环境本身的复杂性。T细胞共刺激受体CD 28也在正常和恶性浆细胞上表达，并且MM中的CD 28表达与不良预后和疾病进展显著相关。与T细胞相反，骨髓瘤细胞中CD 28的活化和功能在很大程度上是不确定的。我们已经发现，抗CD 28单克隆抗体单独直接激活骨髓瘤细胞CD 28可诱导PI 3 K和NF κ B B的激活，抑制MM细胞增殖，并防止血清饥饿和地塞米松（dex）诱导的细胞死亡。与表达CD 28配体CD 80和CD 86的树突状细胞（DC）共培养也会引起CD 28介导的对MM生存和增殖的影响，并且DC似乎优先定位在原发性患者样本中的骨髓瘤浸润内。我们的研究结果表明，以前未描述的骨髓瘤/DC细胞-细胞相互作用，涉及CD 28，可能发挥重要作用，骨髓瘤细胞在骨髓基质中的生存。这些数据也表明CD 28是MM治疗中的潜在治疗靶点。
Although interactions with bone marrow stromal cells are essential for multiple myeloma (MM) cell survival, the specific molecular and cellular elements involved are largely unknown, due in large part to the complexity of the bone marrow microenvironment itself. The T-cell costimulatory receptor CD28 is also expressed on normal and malignant plasma cells, and CD28 expression in MM correlates significantly with poor prognosis and disease progression. In contrast to T cells, activation and function of CD28 in myeloma cells is largely undefined. We have found that direct activation of myeloma cell CD28 by anti-CD28 mAb alone induces activation of PI3K and NF kappa B, suppresses MM cell proliferation, and protects against serum starvation and dexamethasone (dex)-induced cell death. Coculture with dendritic cells (DCs) expressing the CD28 ligands CD80 and CD86 also elicits CD28-mediated effects on MM survival and proliferation, and DCs appear to preferentially localize within myeloma infiltrates in primary patient samples. Our findings suggest a previously undescribed myeloma/DC cell-cell interaction involving CD28 that may play an important role in myeloma cell survival within the bone marrow stroma. These data also point to CD28 as a potential therapeutic target in the treatment of MM.