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Published on: March 30, 2018
Over-expression of CCL3 MIP-1alpha in a blastoid mantle cell lymphoma with hypercalcemia
Norimichi Hattori1, Tsuyoshi Nakamaki, Hirotsugu Ariizumi
1Division of Hematology, Department of Medicine, Showa University School of Medicine, Tokyo, Japan. nhattor@med.showa-u.ac.jp
Insights
Macrophage inflammatory protein-1alpha (MIP-1alpha) produced by blastoid variant mantle cell lymphoma (MCL-BV) cells drives hypercalcemia and aggressive disease. Lowering MIP-1alpha levels led to remission, highlighting its role in MCL pathogenesis.
Area of Science:
- Hematology
- Oncology
- Biochemistry
Background:
- Mantle cell lymphoma (MCL) is a B-cell neoplasm.
- The blastoid variant (MCL-BV) is rare and aggressive.
- Hypercalcemia at diagnosis indicates poor prognosis.
Observation:
- A patient with MCL-BV presented with severe hypercalcemia.
- Elevated serum cytokines including macrophage inflammatory protein-1alpha (MIP-1alpha) were detected.
- MCL cells expressed mRNA for MIP-1alpha, RANKL, TNF-alpha, and IL-6.
Findings:
- MIP-1alpha stimulated MCL cell proliferation in vitro.
- MIP-1alpha is implicated as a local osteoclast-activating factor contributing to hypercalcemia.
- MIP-1alpha may promote an aggressive MCL phenotype via proliferation stimulation.
Implications:
- MIP-1alpha is a potential therapeutic target in MCL-BV.
- Targeting MIP-1alpha may help manage hypercalcemia and aggressive disease in MCL.
- This case highlights the role of cytokines in lymphoma-associated complications.
Abstract:
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.
