title: MCL1 is deregulated in subgroups of diffuse large B-cell lymphoma.
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.
authors.affiliation: Department of Hematology, Oncology and Tumor Immunology, Molecular Cancer Research Center, Charité-Universitätsmedizin Berlin, Germany.
authors.forename: S-S
authors.initials: SS
authors.lastname: Wenzel
authors.forename: M
authors.initials: M
authors.lastname: Grau
authors.forename: C
authors.initials: C
authors.lastname: Mavis
authors.forename: S
authors.initials: S
authors.lastname: Hailfinger
authors.forename: A
authors.initials: A
authors.lastname: Wolf
authors.forename: H
authors.initials: H
authors.lastname: Madle
authors.forename: G
authors.initials: G
authors.lastname: Deeb
authors.forename: B
authors.initials: B
authors.lastname: Dörken
authors.forename: M
authors.initials: M
authors.lastname: Thome
authors.forename: P
authors.initials: P
authors.lastname: Lenz
authors.forename: S
authors.initials: S
authors.lastname: Dirnhofer
authors.forename: F J
authors.initials: FJ
authors.lastname: Hernandez-Ilizaliturri
authors.forename: A
authors.initials: A
authors.lastname: Tzankov
authors.forename: G
authors.initials: G
authors.lastname: Lenz
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use; D055028:Comparative Genomic Hybridization; D020869:Gene Expression Profiling; D006801:Humans; D007150:Immunohistochemistry; D016403:Lymphoma, Large B-Cell, Diffuse / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics*; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D000970:Antineoplastic Agents; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D019253:Proto-Oncogene Proteins c-bcl-2