Division of Hematology, Department of Medicine, Showa University School of Medicine, Tokyo, Japan.
Eur J Haematol. 2010 May;84(5):448-52. doi: 10.1111/j.1600-0609.2009.01405.x. Epub 2010 Dec 24.
We analyzed a case with the blastoid variant of mantle cell lymphoma (MCL-BV), a rare subtype of B-cell lymphoma, presenting with marked hypercalcemia at diagnosis. Enzyme-linked immunosorbent assay (ELISA) showed elevated serum levels of interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha), macrophage inflammatory protein-1alpha (MIP-1alpha), and type I collagen telopeptide, but not parathyroid hormone, calcitriol or parathyroid hormone-related peptide at diagnosis, suggesting local osteoclastic hypercalcemia in this case. By reverse transcription polymerase chain reaction (RT-PCR) analysis, we found predominant expression of mRNA for MIP-1alpha in addition to those for receptor-activator of nuclear-factor kappa B ligand (RANKL), TNF-alpha, and IL-6 in lymphoma cells obtained from the patient. Furthermore, recombinant MIP-1alpha significantly stimulated (3)H-thymidine uptake by isolated MCL cells in vitro. Treatment with intravenous fluids, bisphosphonate, and methylprednisolone followed by combination chemotherapy promptly corrects the hypercalcemia and successfully induced complete remission, which was accompanied by a decrease of these cytokines in the serum, including MIP-1alpha. In the present case, MIP-1alpha, an osteoclast-activating factor produced by mantle lymphoma cells, may contribute to the development of hypercalcemia. It likely acts through RANKL expression in tumor cells and/or stroma cells, as indicated in multiple myeloma (MM) and adult T-cell leukemia/lymphoma (ATLL). Furthermore, MIP-1alpha is also involved in the development of an aggressive phenotype on MCL by stimulating proliferation of these lymphoma cells. In summary, the present study demonstrated that MIP-1alpha is an important factor in the development of both hypercalcemia and an aggressive phenotype in some types of B-cell lymphoma.
我们分析了一例具有母细胞淋巴瘤（MCL-BV）的爆米花样变体的病例，这是一种罕见的 B 细胞淋巴瘤亚型，在诊断时表现出明显的高钙血症。酶联免疫吸附测定（ELISA）显示血清白细胞介素-6（IL-6）、肿瘤坏死因子-α（TNF-α）、巨噬细胞炎症蛋白-1α（MIP-1α）和 I 型胶原肽水平升高，但甲状旁腺激素、钙三醇或甲状旁腺激素相关肽水平不升高，提示该病例存在局部破骨细胞性高钙血症。通过逆转录聚合酶链反应（RT-PCR）分析，我们发现除了受体激活核因子 kappa B 配体（RANKL）、TNF-α 和 IL-6 之外，患者淋巴瘤细胞中还存在 MIP-1α 的主要表达。此外，重组 MIP-1α 显著刺激了体外分离的 MCL 细胞摄取放射性标记的胸腺嘧啶。静脉补液、双膦酸盐和甲基强的松龙治疗后，联合化疗迅速纠正了高钙血症，并成功诱导完全缓解，同时血清中包括 MIP-1α 在内的这些细胞因子水平降低。在本病例中，MIP-1α，一种由母细胞淋巴瘤细胞产生的破骨细胞激活因子，可能导致高钙血症的发生。它可能通过肿瘤细胞和/或基质细胞中的 RANKL 表达起作用，这在多发性骨髓瘤（MM）和成人 T 细胞白血病/淋巴瘤（ATLL）中得到了证实。此外，MIP-1α 还通过刺激这些淋巴瘤细胞的增殖，参与了 MCL 侵袭性表型的发展。总之，本研究表明，MIP-1α 是某些类型 B 细胞淋巴瘤中高钙血症和侵袭性表型发展的重要因素。
