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Lymphoma

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

Leukemia volume 27, pages 1381–1390 (2013)Cite this article

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Abstract

Myeloid cell leukemia-1 (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 with germinal center B-cell-like DLBCL patient samples (P=2.7 × 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 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.

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Acknowledgements

We thank Kerstin Dietze (Charité—Universitätsmedizin Berlin) and Chantal Décaillet (University of Lausanne) for technical assistance. This work was supported by research grants to GL from the Else Kröner-Fresenius-Stiftung, the German Research Foundation (DFG), the Deutsche Krebshilfe and the Berliner Krebsgesellschaft e.V. as well as by a Doctoral Scholarship to M.G. from the Philipps-University Marburg.

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Authors and Affiliations

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

    S-S Wenzel, A Wolf, H Madle, B Dörken & G Lenz

  2. Department of Physics, Philipps University, Marburg, Germany

    M Grau & P Lenz

  3. Department of Medicine, Roswell Park Cancer Institute, Buffalo, USA

    C Mavis & F J Hernandez-Ilizaliturri

  4. Department of Biochemistry, University of Lausanne, Lausanne, Switzerland

    S Hailfinger & M Thome

  5. Department of Pathology, Roswell Park Cancer Institute, Buffalo, USA

    G Deeb

  6. Institute of Pathology, University Hospital, Basel, Switzerland

    S Dirnhofer & A Tzankov

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  1. S-S Wenzel
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Correspondence to G Lenz.

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Wenzel, SS., Grau, M., Mavis, C. et al. MCL1 is deregulated in subgroups of diffuse large B-cell lymphoma. Leukemia 27, 1381–1390 (2013). https://doi.org/10.1038/leu.2012.367

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