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

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Item Type:	Article
Title:	MCL1 is deregulated in subgroups of diffuse large B-cell lymphoma
Creators Name:	Wenzel, S.S., Grau, M., Mavis, C., Hailfinger, S., Wolf, A., Madle, H., Deeb, G., Doerken, B., Thome, M., Lenz, P., Dirnhofer, S., Hernandez-Ilizaliturri, F.J., 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
Source:	Leukemia
ISSN:	0887-6924
Publisher:	Nature Publishing Group
Volume:	27
Number:	6
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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