Genetic polymorphisms of EPHX1, Gsk3 beta, TNFSF8 and myeloma cell DKK-1 expression linked to bone disease in myeloma
LEUKEMIA
Authors: Durie, B. G. M.; Van Ness, B.; Ramos, C.; Stephens, O.; Haznadar, M.; Hoering, A.; Haessler, J.; Katz, M. S.; Mundy, G. R.; Kyle, R. A.; Morgan, G. J.; Crowley, J.; Barlogie, B.; Shaughnessy, J., Jr.
Abstract
Bone disease in myeloma occurs as a result of complex interactions between myeloma cells and the bone marrow microenvironment. A custom-built DNA single nucleotide polymorphism (SNP) chip containing 3404 SNPs was used to test genomic DNA from myeloma patients classified by the extent of bone disease. Correlations identified with a Total Therapy 2 (TT2) (Arkansas) data set were validated with Eastern Cooperative Oncology Group (ECOG) and Southwest Oncology Group (SWOG) data sets. Univariate correlates with bone disease included: EPHX1, IGF1R, IL-4 and Gsk3 beta. SNP signatures were linked to the number of bone lesions, log(2) DKK-1 myeloma cell expression levels and patient survival. Using stepwise multivariate regression analysis, the following SNPs: EPHX1 (P = 0.0026); log(2) DKK-1 expression (P = 0.0046); serum lactic dehydrogenase (LDH) (P = 0.0074); Gsk3 beta (P = 0.02) and TNFSF8 (P = 0.04) were linked to bone disease. This assessment of genetic polymorphisms identifies SNPs with both potential biological relevance and utility in prognostic models of myeloma bone disease. Leukemia (2009) 23, 1913-1919; doi: 10.1038/leu.2009.129; published online 6 August 2009
A novel role for reciprocal CD30-CD30L signaling in the cross-talk between natural killer and dendritic cells
BIOLOGICAL CHEMISTRY
Authors: Simhadri, Vijaya Lakshmi; Hansen, Hinrich P.; Simhadri, Venkateswara R.; Reiners, Katrin S.; Bessler, Martina; Engert, Andreas; von Strandmann, Elke Pogge
Abstract
The interplay between dendritic cells (DCs) and natural killer (NK) cells directs adaptive immune responses. The molecular basis of the cross-talk is largely undefined. Here, we provide evidence for a contribution of CD30 (TNFRSF8) and its ligand CD30L (TNFSF8) expressed on NK cells and DCs, respectively. We demonstrate that CD30-mediated engagement of CD30L induced cytokine secretion from immature DCs via the mitogen-activated protein kinase pathway. Moreover, CD30L engagement promoted differentiation to mature DCs. On the contrary, the engagement of CD30 on NK cells resulted in an NF-kappa B-dependent release of TNF-alpha/IFN-gamma. These data uncover a novel and unexpected role for CD30/CD30L that contributes to proinflammatory immune responses.
COA
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