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.

Nature.com

Clinicopathological features of aggressive B-cell lymphomas including B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell and Burkitt lymphomas: a study of 44 patients from Argentina.

Dec 2012

Bürgesser MV, Gualco G, Diller A, Natkunam Y, Bacchi CE.

Source

Servicio de Patología, Hospital Privado de Córdoba. Córdoba, Argentina.

Abstract

Aggressive B-cell lymphomas incorporate a wide spectrum of lymphomas that pose challenges in diagnosis as well as treatment. We evaluated the clinicopathological features of 44 patients with aggressive B-cell lymphomas which were classified into 3 groups based on the World Health Organization 2008 classification as follows: including 30 cases of diffuse large B-cell lymphoma (DLBCL), 8 cases of Burkitt lymphoma (BL) and 6 cases of B-cell lymphoma, unclassifiable, with features intermediate between Burkitt lymphoma and diffuse large B-cell lymphoma (BCLU). Male predominance was observed in BL and BCLU groups and the mean age varied from 29 years in BL, 61 years in DLBCL and 70 years in BCLU. Patients with BCLU presented at more advanced stages and had a higher international prognostic index. By immunohistochemistry, they shared characteristics of both BL (including more frequent expression of SOX11) and DLBCL. FISH analyses showed three cases with more than one rearrangement: one MYC/BCL2 and two BCL2/BCL6, in addition to which one case with BCL2/IGH translocation and another with MYC rearrangement were also detected. The mean follow-up survival time of BCLU was 6.6 months, which was significantly shorter in comparison to DLBCL (31 months) and BL (30 months), respectively. The importance of recognizing this BCLU group relies on its different clinical course, poor prognosis and shorter survival than DLBCL and BL. An accurate diagnosis is critical for risk stratification and to improve therapeutic approaches and outcomes.

Elsevier - Annals of Diagnostic Pathology

The Hans algorithm failed to predict outcome in patients with diffuse large B-cell lymphoma treated with rituximab.

Oct 2012

Benesova K, Forsterova K, Votavova H, Campr V, Stritesky J, Velenska Z, Prochazka B, Pytlik R, Trneny M.

Abstract

Diffuse large B-cell lymphoma (DLBCL) consists of at least two biologically and pathogenetically different subtypes, the germinal centre B-cell (GCB) and the activated B cell type (ABC). It has been suggested that immunohistochemistry can discriminate these subtypes as well. The aim of this study was to verify the validity of the most commonly used Hans algorithm in patients with DLBCL treated with anthracycline- based chemotherapy with rituximab. Immunohistochemical staining using standard protocols was performed on formalin fixed paraffin-embedded tissues. CD20, CD5, CD23, BCL2, CD10, BCL6, MUM1 and Ki67 antibodies were applied. Out of 120 examined cases 52 patients were evaluated as GCB type and 68 patients as having non-GCB, out of a set of 99 patients treated with immunochemotherapy 45 patients with GCB and 54 patients with non-GCB DLBCL were identified. In this set of patients, there was no statistically significant difference neither in overall survival (OS) (HR 1.47 95% CI 0.51-2.63; p=0.45) nor in progression free survival (PFS) (HR 1.57, 95 % CI 0.76-3.22; p=0.731) between both groups. Keywords: DLBCL, Hans, rituximab, GC, nonGC.

DOI System

PubMed