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MCL1 is deregulated in subgroups of diffuse large B-cell lymphoma

Item Type:Article
Title:MCL1 is deregulated in subgroups of diffuse large B-cell lymphoma
Creators Name:Wenzel, S.S. and Grau, M. and Mavis, C. and Hailfinger, S. and Wolf, A. and Madle, H. and Deeb, G. and Doerken, B. and Thome, M. and Lenz, P. and Dirnhofer, S. and Hernandez-Ilizaliturri, F.J. and Tzankov, A. and Lenz, G.
Abstract:MCL1 is an anti-apoptotic member of the BCL2 family that is deregulated in various solid and hematological malignancies. However, its role in the molecular pathogenesis of diffuse large B-cell lymphoma (DLBCL) is unclear. We analyzed gene expression profiling data from 350 DLBCL patient samples and detected that activated B-cell-like (ABC) DLBCLs express MCL1 at significantly higher levels compared to germinal center B-cell-like (GCB) DLBCL patient samples (p=2.7 x 10(-10)). Immunohistochemistry confirmed high MCL1 protein expression predominantly in ABC DLBCL in an independent patient cohort (n=249; p=0.001). To elucidate molecular mechanisms leading to aberrant MCL1 expression, we analyzed array comparative genomic hybridization (aCGH) data of 203 DLBCL samples and identified recurrent chromosomal gains/amplifications of the MCL1 locus that occurred in 26% of ABC DLBCLs. In addition, aberrant STAT3 signaling contributed to high MCL1 expression in this subtype. Knockdown of MCL1 as well as treatment with the BH3-mimetic obatoclax induced apoptotic cell death in MCL1 positive DLBCL cell lines. In summary, MCL1 is deregulated in a significant fraction of ABC DLBCLs and contributes to therapy resistance. These data suggest that specific inhibition of MCL1 might be utilized therapeutically in a subset of DLBCLs.
Keywords:MCL1, Diffuse Large B-Cell Lymphoma, aCGH, Apoptosis, Therapy Resistance
Publisher:Nature Publishing Group
Page Range:1381-1390
Date:June 2013
Official Publication:https://doi.org/10.1038/leu.2012.367
PubMed:View item in PubMed

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