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

Dec 21, 2012

Wenzel SS, Grau M, Mavis C, Hailfinger S, Wolf A, Madle H, Deeb G, Dörken B, Thome M, Lenz P, Dirnhofer S,Hernandez-Ilizaliturri FJ, Tzankov A, Lenz G.

Source

Department of Hematology, Oncology and Tumor Immunology, Molecular Cancer Research Center, Charité - Universitätsmedizin Berlin, Germany.

Abstract

Keywords: 

MCL1, diffuse large B-cell lymphoma, aCGH, apoptosis, therapy resistance

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.Leukemia accepted article preview online, 21 December 2012; doi:10.1038/leu.2012.367.

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