Browsing by Author "Tzankov, A"

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    Comprehensive gene expression profiling and immunohistochemical studies support application of immunophenotypic algorithm for molecular subtype classification in diffuse large B-cell lymphoma: a report from the International DLBCL Rituximab-CHOP Consortium Program Study.
    (Leukemia, 2012-09) Visco, C; Li, Y; Xu-Monette, ZY; Miranda, RN; Green, TM; Li, Y; Tzankov, A; Wen, W; Liu, W-M; Kahl, BS; d'Amore, ESG; Montes-Moreno, S; Dybkær, K; Chiu, A; Tam, W; Orazi, A; Zu, Y; Bhagat, G; Winter, JN; Wang, H-Y; O'Neill, S; Dunphy, CH; Hsi, ED; Zhao, XF; Go, RS; Choi, WWL; Zhou, F; Czader, M; Tong, J; Zhao, X; van Krieken, JH; Huang, Q; Ai, W; Etzell, J; Ponzoni, M; Ferreri, AJM; Piris, MA; Møller, MB; Bueso-Ramos, CE; Medeiros, LJ; Wu, L; Young, KH
    Gene expression profiling (GEP) has stratified diffuse large B-cell lymphoma (DLBCL) into molecular subgroups that correspond to different stages of lymphocyte development-namely germinal center B-cell like and activated B-cell like. This classification has prognostic significance, but GEP is expensive and not readily applicable into daily practice, which has lead to immunohistochemical algorithms proposed as a surrogate for GEP analysis. We assembled tissue microarrays from 475 de novo DLBCL patients who were treated with rituximab-CHOP chemotherapy. All cases were successfully profiled by GEP on formalin-fixed, paraffin-embedded tissue samples. Sections were stained with antibodies reactive with CD10, GCET1, FOXP1, MUM1 and BCL6 and cases were classified following a rationale of sequential steps of differentiation of B cells. Cutoffs for each marker were obtained using receiver-operating characteristic curves, obviating the need for any arbitrary method. An algorithm based on the expression of CD10, FOXP1 and BCL6 was developed that had a simpler structure than other recently proposed algorithms and 92.6% concordance with GEP. In multivariate analysis, both the International Prognostic Index and our proposed algorithm were significant independent predictors of progression-free and overall survival. In conclusion, this algorithm effectively predicts prognosis of DLBCL patients matching GEP subgroups in the era of rituximab therapy.
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    Loss of PRDM1/BLIMP-1 function contributes to poor prognosis of activated B-cell-like diffuse large B-cell lymphoma.
    (Leukemia, 2017-03) Xia, Y; Xu-Monette, ZY; Tzankov, A; Li, X; Manyam, GC; Murty, V; Bhagat, G; Zhang, S; Pasqualucci, L; Visco, C; Dybkaer, K; Chiu, A; Orazi, A; Zu, Y; Richards, KL; Hsi, ED; Choi, WWL; van Krieken, JH; Huh, J; Ponzoni, M; Ferreri, AJM; Møller, MB; Parsons, BM; Winter, JN; Piris, MA; Westin, J; Fowler, N; Miranda, RN; Ok, CY; Li, Y; Li, J; Medeiros, LJ; Young, KH
    PRDM1/BLIMP-1, a master regulator of plasma-cell differentiation, is frequently inactivated in activated B-cell-like (ABC) diffuse large B-cell lymphoma (DLBCL) patients. Little is known about its genetic aberrations and relevant clinical implications. A large series of patients with de novo DLBCL was effectively evaluated for PRDM1/BLIMP-1 deletion, mutation, and protein expression. BLIMP-1 expression was frequently associated with the ABC phenotype and plasmablastic morphologic subtype of DLBCL, yet 63% of the ABC-DLBCL patients were negative for BLIMP-1 protein expression. In these patients, loss of BLIMP-1 was associated with Myc overexpression and decreased expression of p53 pathway molecules. In addition, homozygous PRDM1 deletions and PRDM1 mutations within exons 1 and 2, which encode for domains crucial for transcriptional repression, were found to show a poor prognostic impact in patients with ABC-DLBCL but not in those with germinal center B-cell-like DLBCL (GCB-DLBCL). Gene expression profiling revealed that loss of PRDM1/BLIMP-1 expression correlated with a decreased plasma-cell differentiation signature and upregulation of genes involved in B-cell receptor signaling and tumor-cell proliferation. In conclusion, these results provide novel clinical and biological insight into the tumor-suppressive role of PRDM1/BLIMP-1 in ABC-DLBCL patients and suggest that loss of PRDM1/BLIMP-1 function contributes to the overall poor prognosis of ABC-DLBCL patients.