PRDM1/BLIMP1 is commonly inactivated in anaplastic large T-cell lymphoma by Michela Boi, Andrea Rinaldi, Ivo Kwee, Paola Bonetti, Maria Todaro, Fabrizio.

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PRDM1/BLIMP1 is commonly inactivated in anaplastic large T-cell lymphoma by Michela Boi, Andrea Rinaldi, Ivo Kwee, Paola Bonetti, Maria Todaro, Fabrizio Tabbò, Roberto Piva, Paola M. V. Rancoita, András Matolcsy, Botond Timar, Thomas Tousseyn, Socorro Maria Rodríguez-Pinilla, Miguel A. Piris, Sílvia Beà, Elias Campo, Govind Bhagat, Steven H. Swerdlow, Andreas Rosenwald, Maurilio Ponzoni, Ken H. Young, Pier Paolo Piccaluga, Reinhard Dummer, Stefano Pileri, Emanuele Zucca, Giorgio Inghirami, and Francesco Bertoni Blood Volume 122(15):2683-2693 October 10, 2013 ©2013 by American Society of Hematology

Genomic aberrations in ALCL samples. Genomic aberrations in ALCL samples. (A) Frequency of DNA gains (up) and losses (down) observed in 64 systemic ALCL (top panel), 31 ALK−ALCL (middle panel), and 33 ALK+ALCL samples (bottom panel). Red represents gains and blue represents losses. X-axis represents chromosome localization and physical mapping; y-axis, proportion of cases showing the aberrations. (B-C) Representation of focal aberrations in ALCL samples. Analysis via GISTIC of copy number gains (left) and losses (right) for the 64 ALCL samples and only for the 31 ALK−ALCL samples. False-discovery rate q values are plotted along the x-axis with chromosomal position along the y-axis. Altered regions with significant levels exceeding the vertical green line (significance threshold) were deemed significant. Chromosomal positions are shown for each significant region on the right side of the plots. Michela Boi et al. Blood 2013;122:2683-2693 ©2013 by American Society of Hematology

PRDM1 gene is inactivated in ALCL samples. PRDM1 gene is inactivated in ALCL samples. (A) Representation of the aberrations, and their size, affecting the PRDM1 locus (6q21). Blue bars represent loss; light blue bars represent homozygous deletion (hdel). (B) Results of sequencing and mutational analysis of PRDM1 coding exons in 46 ALCL samples (31 ALK− and 15 ALK+ samples) and in 7 ALCL cell lines (5 ALK+ and 1 ALK− cell line and 1 cALCL). Red triangles are new mutations in 2 different ALK− samples. (C) View of the single nucleotide changes in different sequences. (D) Immunohistochemistry results for BLIMP1 staining: BLIMP1 staining was evaluated on TMA obtained from an independent series of ALCL samples. TMA samples were considered negative or positive for BLIMP1 depending on the intensity of the staining. A representative case for each condition, BLIMP1 negative (left panel), BLIMP1 positive only at cytoplasmic level (middle panel), BLIMP1 positive only at a nuclear level (right panel), is reported (magnification, ×40). TMA, tissue microarray. Michela Boi et al. Blood 2013;122:2683-2693 ©2013 by American Society of Hematology

PRDM1 is a tumor suppressor gene in an in vitro model of ALCL PRDM1 is a tumor suppressor gene in an in vitro model of ALCL. (A) PRDM1/BLIMP1 mRNA and protein level after infection with empty vector (pWPI) or vector for BLIMP1 reexpression (pWPI-HA-BLIMP1). PRDM1 is a tumor suppressor gene in an in vitro model of ALCL. (A) PRDM1/BLIMP1 mRNA and protein level after infection with empty vector (pWPI) or vector for BLIMP1 reexpression (pWPI-HA-BLIMP1). (B) Percentage of GFP-positive cells after infection at 72 hours and 96 hours. (C) Percentage of growing cells after infection at 72 hours. *P = .017. (D) Growth curve after infection, cells counted at days 3, 5, and 7 after infection. (E) Percentage of dead cells after infection at 72 hours and 96 hours. (F) Cell-cycle profile after infection. Michela Boi et al. Blood 2013;122:2683-2693 ©2013 by American Society of Hematology

Hierarchical clustering of samples analyzed with GEP Hierarchical clustering of samples analyzed with GEP. GEP analysis was performed in untreated Supm2-TS cells (n = 3), Supm2-TS cells 72 hours after infection with empty vector (pWPI; n = 3) and Supm2-TS cells after infection with lentivirus for BLIMP1 recon... Hierarchical clustering of samples analyzed with GEP. GEP analysis was performed in untreated Supm2-TS cells (n = 3), Supm2-TS cells 72 hours after infection with empty vector (pWPI; n = 3) and Supm2-TS cells after infection with lentivirus for BLIMP1 reconstitution (pWPI-HA-BLIMP1; n = 3). Michela Boi et al. Blood 2013;122:2683-2693 ©2013 by American Society of Hematology

PRDM1 is a tumor suppressor gene in vivo. PRDM1 is a tumor suppressor gene in vivo. (A) Percentage of GFP-positive cells in tumors explanted from mice infected with empty vector (pWPI) or with vector for BLIMP1 reexpression (pWPI-HA-BLIMP1). (B) Protein levels of BLIMP1 and GFP in tumors explanted from mice at day 20. A vertical line has been inserted to indicate a repositioned gel lane. (C) Xenograft growth curves of infected cells in NSG mice. Michela Boi et al. Blood 2013;122:2683-2693 ©2013 by American Society of Hematology

Distribution of main genomic aberration in ALK+ and ALK-ALCL and their impact on outcome. Distribution of main genomic aberration in ALK+ and ALK-ALCL and their impact on outcome. Heatmap with the relative distribution of the most common lesions detected in ALCL samples (A) and Kaplan-Meier graph showing OS in systemic ALCL according to ALK status and to the presence of PRDM1 inactivation and/or TP53 loss (B). In panel A: red, presence; gray, absence. In panel B: x-axis, months; y-axis, percentage of alive patients. Michela Boi et al. Blood 2013;122:2683-2693 ©2013 by American Society of Hematology