Faculty Profiles - ENNISHI Daisuke

Papers - ENNISHI Daisuke

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CREBBP Inactivation Promotes the Development of HDAC3-Dependent Lymphomas. International journal

Yanwen Jiang, Ana Ortega-Molina, Huimin Geng, Hsia-Yuan Ying, Katerina Hatzi, Sara Parsa, Dylan McNally, Ling Wang, Ashley S Doane, Xabier Agirre, Matt Teater, Cem Meydan, Zhuoning Li, David Poloway, Shenqiu Wang, Daisuke Ennishi, David W Scott, Kristy R Stengel, Janice E Kranz, Edward Holson, Sneh Sharma, James W Young, Chi-Shuen Chu, Robert G Roeder, Rita Shaknovich, Scott W Hiebert, Randy D Gascoyne, Wayne Tam, Olivier Elemento, Hans-Guido Wendel, Ari M Melnick

Cancer discovery 7 ( 1 ) 38 - 53 2017.1

Language：English Publishing type：Research paper (scientific journal)

Somatic mutations in CREBBP occur frequently in B-cell lymphoma. Here, we show that loss of CREBBP facilitates the development of germinal center (GC)-derived lymphomas in mice. In both human and murine lymphomas, CREBBP loss-of-function resulted in focal depletion of enhancer H3K27 acetylation and aberrant transcriptional silencing of genes that regulate B-cell signaling and immune responses, including class II MHC. Mechanistically, CREBBP-regulated enhancers are counter-regulated by the BCL6 transcriptional repressor in a complex with SMRT and HDAC3, which we found to bind extensively to MHC class II loci. HDAC3 loss-of-function rescued repression of these enhancers and corresponding genes, including MHC class II, and more profoundly suppressed CREBBP-mutant lymphomas in vitro and in vivo Hence, CREBBP loss-of-function contributes to lymphomagenesis by enabling unopposed suppression of enhancers by BCL6/SMRT/HDAC3 complexes, suggesting HDAC3-targeted therapy as a precision approach for CREBBP-mutant lymphomas. SIGNIFICANCE: Our findings establish the tumor suppressor function of CREBBP in GC lymphomas in which CREBBP mutations disable acetylation and result in unopposed deacetylation by BCL6/SMRT/HDAC3 complexes at enhancers of B-cell signaling and immune response genes. Hence, inhibition of HDAC3 can restore the enhancer histone acetylation and may serve as a targeted therapy for CREBBP-mutant lymphomas. Cancer Discov; 7(1); 38-53. ©2016 AACR.See related commentary by Höpken, p. 14This article is highlighted in the In This Issue feature, p. 1.

DOI： 10.1158/2159-8290.CD-16-0975

Histological Transformation and Progression in Follicular Lymphoma: A Clonal Evolution Study. International journal

Robert Kridel, Fong Chun Chan, Anja Mottok, Merrill Boyle, Pedro Farinha, King Tan, Barbara Meissner, Ali Bashashati, Andrew McPherson, Andrew Roth, Karey Shumansky, Damian Yap, Susana Ben-Neriah, Jamie Rosner, Maia A Smith, Cydney Nielsen, Eva Giné, Adele Telenius, Daisuke Ennishi, Andrew Mungall, Richard Moore, Ryan D Morin, Nathalie A Johnson, Laurie H Sehn, Thomas Tousseyn, Ahmet Dogan, Joseph M Connors, David W Scott, Christian Steidl, Marco A Marra, Randy D Gascoyne, Sohrab P Shah

PLoS medicine 13 ( 12 ) e1002197 2016.12

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: Follicular lymphoma (FL) is an indolent, yet incurable B cell malignancy. A subset of patients experience an increased mortality rate driven by two distinct clinical end points: histological transformation and early progression after immunochemotherapy. The nature of tumor clonal dynamics leading to these clinical end points is poorly understood, and previously determined genetic alterations do not explain the majority of transformed cases or accurately predict early progressive disease. We contend that detailed knowledge of the expansion patterns of specific cell populations plus their associated mutations would provide insight into therapeutic strategies and disease biology over the time course of FL clinical histories. METHODS AND FINDINGS: Using a combination of whole genome sequencing, targeted deep sequencing, and digital droplet PCR on matched diagnostic and relapse specimens, we deciphered the constituent clonal populations in 15 transformation cases and 6 progression cases, and measured the change in clonal population abundance over time. We observed widely divergent patterns of clonal dynamics in transformed cases relative to progressed cases. Transformation specimens were generally composed of clones that were rare or absent in diagnostic specimens, consistent with dramatic clonal expansions that came to dominate the transformation specimens. This pattern was independent of time to transformation and treatment modality. By contrast, early progression specimens were composed of clones that were already present in the diagnostic specimens and exhibited only moderate clonal dynamics, even in the presence of immunochemotherapy. Analysis of somatic mutations impacting 94 genes was undertaken in an extension cohort consisting of 395 samples from 277 patients in order to decipher disrupted biology in the two clinical end points. We found 12 genes that were more commonly mutated in transformed samples than in the preceding FL tumors, including TP53, B2M, CCND3, GNA13, S1PR2, and P2RY8. Moreover, ten genes were more commonly mutated in diagnostic specimens of patients with early progression, including TP53, BTG1, MKI67, and XBP1. CONCLUSIONS: Our results illuminate contrasting modes of evolution shaping the clinical histories of transformation and progression. They have implications for interpretation of evolutionary dynamics in the context of treatment-induced selective pressures, and indicate that transformation and progression will require different clinical management strategies.

DOI： 10.1371/journal.pmed.1002197

Loss of the HVEM Tumor Suppressor in Lymphoma and Restoration by Modified CAR-T Cells. International journal

Michael Boice, Darin Salloum, Frederic Mourcin, Viraj Sanghvi, Rada Amin, Elisa Oricchio, Man Jiang, Anja Mottok, Nicolas Denis-Lagache, Giovanni Ciriello, Wayne Tam, Julie Teruya-Feldstein, Elisa de Stanchina, Wing C Chan, Sami N Malek, Daisuke Ennishi, Renier J Brentjens, Randy D Gascoyne, Michel Cogné, Karin Tarte, Hans-Guido Wendel

Cell 167 ( 2 ) 405 - 418 2016.10

Language：English Publishing type：Research paper (scientific journal)

The HVEM (TNFRSF14) receptor gene is among the most frequently mutated genes in germinal center lymphomas. We report that loss of HVEM leads to cell-autonomous activation of B cell proliferation and drives the development of GC lymphomas in vivo. HVEM-deficient lymphoma B cells also induce a tumor-supportive microenvironment marked by exacerbated lymphoid stroma activation and increased recruitment of T follicular helper (TFH) cells. These changes result from the disruption of inhibitory cell-cell interactions between the HVEM and BTLA (B and T lymphocyte attenuator) receptors. Accordingly, administration of the HVEM ectodomain protein (solHVEM(P37-V202)) binds BTLA and restores tumor suppression. To deliver solHVEM to lymphomas in vivo, we engineered CD19-targeted chimeric antigen receptor (CAR) T cells that produce solHVEM locally and continuously. These modified CAR-T cells show enhanced therapeutic activity against xenografted lymphomas. Hence, the HVEM-BTLA axis opposes lymphoma development, and our study illustrates the use of CAR-T cells as "micro-pharmacies" able to deliver an anti-cancer protein.

DOI： 10.1016/j.cell.2016.08.032

Impact of dual expression of MYC and BCL2 by immunohistochemistry on the risk of CNS relapse in DLBCL. International journal

Kerry J Savage, Graham W Slack, Anja Mottok, Laurie H Sehn, Diego Villa, Roopesh Kansara, Robert Kridel, Christian Steidl, Daisuke Ennishi, King L Tan, Susana Ben-Neriah, Nathalie A Johnson, Joseph M Connors, Pedro Farinha, David W Scott, Randy D Gascoyne

Blood 127 ( 18 ) 2182 - 8 2016.5

Language：English Publishing type：Research paper (scientific journal)

Dual expression of MYC and BCL2 by immunohistochemistry (IHC) is associated with poor outcome in diffuse large B-cell lymphoma (DLBCL). Dual translocation of MYC and BCL2, so-called "double-hit lymphoma," has been associated with a high risk of central nervous system (CNS) relapse; however, the impact of dual expression of MYC and BCL2 (dual expressers) on the risk of CNS relapse remains unknown. Pretreatment formalin-fixed paraffin-embedded DLBCL biopsies derived from patients subsequently treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) were assembled on tissue microarrays from 2 studies and were evaluated for expression of MYC and BCL2 by IHC. In addition, cell of origin was determined by IHC and the Lymph2Cx gene expression assay in a subset of patients. We identified 428 patients who met the inclusion criteria. By the recently described CNS risk score (CNS-International Prognostic Index [CNS-IPI]), 34% were low risk (0 to 1), 45% were intermediate risk (2 to 3), and 21% were high risk (4 or greater). With a median follow-up of 6.8 years, the risk of CNS relapse was higher in dual expressers compared with non-dual expressers (2-year risk, 9.7% vs 2.2%; P = .001). Patients with activated B-cell or non-germinal center B-cell type DLBCL also had an increased risk of CNS relapse. However, in multivariate analysis, only dual expresser status and CNS-IPI were associated with CNS relapse. Dual expresser MYC(+) BCL2(+) DLBCL defines a group at high risk of CNS relapse, independent of CNS-IPI score and cell of origin. Dual expresser status may help to identify a high-risk group who should undergo CNS-directed evaluation and consideration of prophylactic strategies.

DOI： 10.1182/blood-2015-10-676700

Cell of origin of transformed follicular lymphoma. International journal

Robert Kridel, Anja Mottok, Pedro Farinha, Susana Ben-Neriah, Daisuke Ennishi, Yvonne Zheng, Elizabeth A Chavez, Hennady P Shulha, King Tan, Fong Chun Chan, Merrill Boyle, Barbara Meissner, Adele Telenius, Laurie H Sehn, Marco A Marra, Sohrab P Shah, Christian Steidl, Joseph M Connors, David W Scott, Randy D Gascoyne

Blood 126 ( 18 ) 2118 - 27 2015.10

Language：English Publishing type：Research paper (scientific journal)

Follicular lymphoma (FL) is an indolent disease but transforms in 2% to 3% of patients per year into aggressive, large cell lymphoma, a critical event in the course of the disease associated with increased lymphoma-related mortality. Early transformation cannot be accurately predicted at the time of FL diagnosis and the biology of transformed FL (TFL) is poorly understood. Here, we assembled a cohort of 126 diagnostic FL specimens including 40 patients experiencing transformation (<5 years) and 86 patients not experiencing transformation for at least 5 years. In addition, we assembled an overlapping cohort of 155 TFL patients, including 114 cases for which paired samples were available, and assessed temporal changes of routinely available biomarkers, outcome after transformation, as well as molecular subtypes of TFL. We report that the expression of IRF4 is an independent predictor of early transformation (Hazard ratio, 13.3; P < .001). We also show that composite histology at the time of transformation predicts favorable prognosis. Moreover, applying the Lymph2Cx digital gene expression assay for diffuse large B-cell lymphoma (DLBCL) cell-of-origin determination to 110 patients with DLBCL-like TFL, we demonstrate that TFL is of the germinal-center B-cell-like subtype in the majority of cases (80%) but that a significant proportion of cases is of the activated B-cell-like (ABC) subtype (16%). These latter cases are commonly negative for BCL2 translocation and arise preferentially from BCL2 translocation-negative and/or IRF4-expressing FLs. Our study demonstrates the existence of molecular heterogeneity in TFL as well as its relationship to the antecedent FL.

DOI： 10.1182/blood-2015-06-649905

The histone lysine methyltransferase KMT2D sustains a gene expression program that represses B cell lymphoma development. International journal

Ana Ortega-Molina, Isaac W Boss, Andres Canela, Heng Pan, Yanwen Jiang, Chunying Zhao, Man Jiang, Deqing Hu, Xabier Agirre, Itamar Niesvizky, Ji-Eun Lee, Hua-Tang Chen, Daisuke Ennishi, David W Scott, Anja Mottok, Christoffer Hother, Shichong Liu, Xing-Jun Cao, Wayne Tam, Rita Shaknovich, Benjamin A Garcia, Randy D Gascoyne, Kai Ge, Ali Shilatifard, Olivier Elemento, Andre Nussenzweig, Ari M Melnick, Hans-Guido Wendel

Nature medicine 21 ( 10 ) 1199 - 208 2015.10

Language：English Publishing type：Research paper (scientific journal)

The gene encoding the lysine-specific histone methyltransferase KMT2D has emerged as one of the most frequently mutated genes in follicular lymphoma and diffuse large B cell lymphoma; however, the biological consequences of KMT2D mutations on lymphoma development are not known. Here we show that KMT2D functions as a bona fide tumor suppressor and that its genetic ablation in B cells promotes lymphoma development in mice. KMT2D deficiency also delays germinal center involution and impedes B cell differentiation and class switch recombination. Integrative genomic analyses indicate that KMT2D affects methylation of lysine 4 on histone H3 (H3K4) and expression of a set of genes, including those in the CD40, JAK-STAT, Toll-like receptor and B cell receptor signaling pathways. Notably, other KMT2D target genes include frequently mutated tumor suppressor genes such as TNFAIP3, SOCS3 and TNFRSF14. Therefore, KMT2D mutations may promote malignant outgrowth by perturbing the expression of tumor suppressor genes that control B cell-activating pathways.

DOI： 10.1038/nm.3943

Prognostic Significance of Diffuse Large B-Cell Lymphoma Cell of Origin Determined by Digital Gene Expression in Formalin-Fixed Paraffin-Embedded Tissue Biopsies. International journal

David W Scott, Anja Mottok, Daisuke Ennishi, George W Wright, Pedro Farinha, Susana Ben-Neriah, Robert Kridel, Garrett S Barry, Christoffer Hother, Pau Abrisqueta, Merrill Boyle, Barbara Meissner, Adele Telenius, Kerry J Savage, Laurie H Sehn, Graham W Slack, Christian Steidl, Louis M Staudt, Joseph M Connors, Lisa M Rimsza, Randy D Gascoyne

Journal of clinical oncology : official journal of the American Society of Clinical Oncology 33 ( 26 ) 2848 - 56 2015.9

Language：English Publishing type：Research paper (scientific journal)

PURPOSE: To evaluate the prognostic impact of cell-of-origin (COO) subgroups, assigned using the recently described gene expression-based Lymph2Cx assay in comparison with International Prognostic Index (IPI) score and MYC/BCL2 coexpression status (dual expressers). PATIENTS AND METHODS: Reproducibility of COO assignment using the Lymph2Cx assay was tested employing repeated sampling within tumor biopsies and changes in reagent lots. The assay was then applied to pretreatment formalin-fixed paraffin-embedded tissue (FFPET) biopsies from 344 patients with de novo diffuse large B-cell lymphoma (DLBCL) uniformly treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) at the British Columbia Cancer Agency. MYC and BCL2 protein expression was assessed using immunohistochemistry on tissue microarrays. RESULTS: The Lymph2Cx assay provided concordant COO calls in 96% of 49 repeatedly sampled tumor biopsies and in 100% of 83 FFPET biopsies tested across reagent lots. Critically, no frank misclassification (activated B-cell-like DLBCL to germinal center B-cell-like DLBCL or vice versa) was observed. Patients with activated B-cell-like DLBCL had significantly inferior outcomes compared with patients with germinal center B-cell-like DLBCL (log-rank P < .001 for time to progression, progression-free survival, disease-specific survival, and overall survival). In pairwise multivariable analyses, COO was associated with outcomes independent of IPI score and MYC/BCL2 immunohistochemistry. The prognostic significance of COO was particularly evident in patients with intermediate IPI scores and the non-MYC-positive/BCL2-positive subgroup (log-rank P < .001 for time to progression). CONCLUSION: Assignment of DLBCL COO by the Lymph2Cx assay using FFPET biopsies identifies patient groups with significantly different outcomes after R-CHOP, independent of IPI score and MYC/BCL2 dual expression.

DOI： 10.1200/JCO.2014.60.2383

Integration of gene mutations in risk prognostication for patients receiving first-line immunochemotherapy for follicular lymphoma: a retrospective analysis of a prospective clinical trial and validation in a population-based registry. International journal

Alessandro Pastore, Vindi Jurinovic, Robert Kridel, Eva Hoster, Annette M Staiger, Monika Szczepanowski, Christiane Pott, Nadja Kopp, Mark Murakami, Heike Horn, Ellen Leich, Alden A Moccia, Anja Mottok, Ashwini Sunkavalli, Paul Van Hummelen, Matthew Ducar, Daisuke Ennishi, Hennady P Shulha, Christoffer Hother, Joseph M Connors, Laurie H Sehn, Martin Dreyling, Donna Neuberg, Peter Möller, Alfred C Feller, Martin L Hansmann, Harald Stein, Andreas Rosenwald, German Ott, Wolfram Klapper, Michael Unterhalt, Wolfgang Hiddemann, Randy D Gascoyne, David M Weinstock, Oliver Weigert

The Lancet. Oncology 16 ( 9 ) 1111 - 1122 2015.9

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: Follicular lymphoma is a clinically and genetically heterogeneous disease, but the prognostic value of somatic mutations has not been systematically assessed. We aimed to improve risk stratification of patients receiving first-line immunochemotherapy by integrating gene mutations into a prognostic model. METHODS: We did DNA deep sequencing to retrospectively analyse the mutation status of 74 genes in 151 follicular lymphoma biopsy specimens that were obtained from patients within 1 year before beginning immunochemotherapy consisting of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). These patients were recruited between May 4, 2000, and Oct 20, 2010, as part of a phase 3 trial (GLSG2000). Eligible patients had symptomatic, advanced stage follicular lymphoma and were previously untreated. The primary endpoints were failure-free survival (defined as less than a partial remission at the end of induction, relapse, progression, or death) and overall survival calculated from date of treatment initiation. Median follow-up was 7·7 years (IQR 5·5-9·3). Mutations and clinical factors were incorporated into a risk model for failure-free survival using multivariable L1-penalised Cox regression. We validated the risk model in an independent population-based cohort of 107 patients with symptomatic follicular lymphoma considered ineligible for curative irradiation. Pretreatment biopsies were taken between Feb 24, 2004, and Nov 24, 2009, within 1 year before beginning first-line immunochemotherapy consisting of rituximab, cyclophosphamide, vincristine, and prednisone (R-CVP). Median follow-up was 6·7 years (IQR 5·7-7·6). FINDINGS: We established a clinicogenetic risk model (termed m7-FLIPI) that included the mutation status of seven genes (EZH2, ARID1A, MEF2B, EP300, FOXO1, CREBBP, and CARD11), the Follicular Lymphoma International Prognostic Index (FLIPI), and Eastern Cooperative Oncology Group (ECOG) performance status. In the training cohort, m7-FLIPI defined a high-risk group (28%, 43/151) with 5-year failure-free survival of 38·29% (95% CI 25·31-57·95) versus 77·21% (95% CI 69·21-86·14) for the low-risk group (hazard ratio [HR] 4·14, 95% CI 2·47-6·93; p<0·0001; bootstrap-corrected HR 2·02), and outperformed a prognostic model of only gene mutations (HR 3·76, 95% CI 2·10-6·74; p<0·0001; bootstrap-corrected HR 1·57). The positive predictive value and negative predictive value for 5-year failure-free survival were 64% and 78%, respectively, with a C-index of 0·80 (95% CI 0·71-0·89). In the validation cohort, m7-FLIPI again defined a high-risk group (22%, 24/107) with 5-year failure-free survival of 25·00% (95% CI 12·50-49·99) versus 68·24% (58·84-79·15) in the low-risk group (HR 3·58, 95% CI 2·00-6·42; p<0.0001). The positive predictive value for 5-year failure-free survival was 72% and 68% for negative predictive value, with a C-index of 0·79 (95% CI 0·69-0·89). In the validation cohort, risk stratification by m7-FLIPI outperformed FLIPI alone (HR 2·18, 95% CI 1·21-3·92), and FLIPI combined with ECOG performance status (HR 2·03, 95% CI 1·12-3·67). INTERPRETATION: Integration of the mutational status of seven genes with clinical risk factors improves prognostication for patients with follicular lymphoma receiving first-line immunochemotherapy and is a promising approach to identify the subset at highest risk of treatment failure. FUNDING: Deutsche Krebshilfe, Terry Fox Research Institute.

DOI： 10.1016/S1470-2045(15)00169-2

Array comparative genomic hybridization reveals similarities between nodular lymphocyte predominant Hodgkin lymphoma and T cell/histiocyte rich large B cell lymphoma. International journal

Sylvia Hartmann, Claudia Döring, Emily Vucic, Fong Chun Chan, Daisuke Ennishi, Thomas Tousseyn, Christiane de Wolf-Peeters, Sven Perner, Iwona Wlodarska, Christian Steidl, Randy D Gascoyne, Martin-Leo Hansmann

British journal of haematology 169 ( 3 ) 415 - 22 2015.5

Language：English Publishing type：Research paper (scientific journal)

Nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) and T cell/histiocyte rich large B cell lymphoma (THRLBCL) usually affect middle-aged men, show tumour cells with a B cell phenotype and a low tumour cell content. Whereas the clinical behaviour of NLPHL is indolent, THRLBCL presents with advanced stage disease and an aggressive behaviour. In the present study, array comparative genomic hybridization was performed in seven typical NLPHL, four THRLBCL-like NLPHL variants, six THRLBCL and four diffuse large B cell lymphomas (DLBCL) derived from NLPHL. The number of genomic aberrations was higher in THRLBCL compared with typical and THRLBCL-like variant of NLPHL. Gains of 2p16.1 and losses of 2p11.2 and 9p11.2 were commonly observed in typical and THRLBCL-like variants of NLPHL as well as THRLBCL. Gains of 2p16.1, affecting the REL locus were confirmed in an independent cohort. Expression of the REL protein was observed at similar frequencies in typical and THRLBCL-like variant of NLPHL as well as THRLBCL (33-38%). In conclusion, the present study reveals further similarities between NLPHL and THRLBCL on the genomic level, confirming that these entities are part of a pathobiological spectrum with common molecular features, but varying clinical presentations.

DOI： 10.1111/bjh.13310

Comprehensive miRNA sequence analysis reveals survival differences in diffuse large B-cell lymphoma patients. International journal

Emilia L Lim, Diane L Trinh, David W Scott, Andy Chu, Martin Krzywinski, Yongjun Zhao, A Gordon Robertson, Andrew J Mungall, Jacqueline Schein, Merrill Boyle, Anja Mottok, Daisuke Ennishi, Nathalie A Johnson, Christian Steidl, Joseph M Connors, Ryan D Morin, Randy D Gascoyne, Marco A Marra

Genome biology 16 18 - 18 2015.1

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: Diffuse large B-cell lymphoma (DLBCL) is an aggressive disease, with 30% to 40% of patients failing to be cured with available primary therapy. microRNAs (miRNAs) are RNA molecules that attenuate expression of their mRNA targets. To characterize the DLBCL miRNome, we sequenced miRNAs from 92 DLBCL and 15 benign centroblast fresh frozen samples and from 140 DLBCL formalin-fixed, paraffin-embedded tissue samples for validation. RESULTS: We identify known and candidate novel miRNAs, 25 of which are associated with survival independently of cell-of-origin and International Prognostic Index scores, which are established indicators of outcome. Of these 25 miRNAs, six miRNAs are significantly associated with survival in our validation cohort. Abundant expression of miR-28-5p, miR-214-5p, miR-339-3p, and miR-5586-5p is associated with superior outcome, while abundant expression of miR-324-5p and NOVELM00203M is associated with inferior outcome. Comparison of DLBCL miRNA-seq expression profiles with those from other cancer types identifies miRNAs that were more abundant in B-cell contexts. Unsupervised clustering of miRNAs identifies two clusters of patients that have distinct differences in their outcomes. Our integrative miRNA and mRNA expression analyses reveal that miRNAs increased in abundance in DLBCL appear to regulate the expression of genes involved in metabolism, cell cycle, and protein modification. Additionally, these miRNAs, including one candidate novel miRNA, miR-10393-3p, appear to target chromatin modification genes that are frequent targets of somatic mutation in non-Hodgkin lymphomas. CONCLUSIONS: Our comprehensive sequence analysis of the DLBCL miRNome identifies candidate novel miRNAs and miRNAs associated with survival, reinforces results from previous mutational analyses, and reveals regulatory networks of significance for lymphomagenesis.

DOI： 10.1186/s13059-014-0568-y

Duodenal follicular lymphoma: comprehensive gene expression analysis with insights into pathogenesis. International journal

Katsuyoshi Takata, Motohiko Tanino, Daisuke Ennishi, Akira Tari, Yasuharu Sato, Hiroyuki Okada, Yoshinobu Maeda, Naoe Goto, Hiroshi Araki, Mai Harada, Midori Ando, Masaya Iwamuro, Mitsune Tanimoto, Kazuhide Yamamoto, Randy D Gascoyne, Tadashi Yoshino

Cancer science 105 ( 5 ) 608 - 15 2014.5

Language：English Publishing type：Research paper (scientific journal)

Follicular lymphoma (FL) of the gastrointestinal tract, particularly duodenal follicular lymphoma (DFL), is a rare variant of FL with indolent clinical behavior, and this disease is included in the 2008 World Health Organization classification system. In contrast to nodal follicular lymphoma (NFL), DFL occurs most frequently in the second part of the duodenum, lacks follicular dendritic cell meshworks and has memory B-cell characteristics. However, its molecular pathogenesis is still unclear. In the present study, we examined 10 DFL, 18 NFL and 10 gastric MALT lymphoma samples using gene expression analysis. Quantitative RT-PCR experiments and immunohistochemical analysis for 72 formalin-fixed, paraffin-embedded tissues from an independent series, including 32 DFL, 19 gastric MALT lymphoma and 27 NFL samples, were performed for validation of microarray data. Gene expression profiles of the three lymphoma types were compared using 2918 differentially expressed genes (DEG) and results suggested that DFL shares characteristics of MALT lymphoma. Among these DEG, CCL20 and MAdCAM-1 were upregulated in DFL and MALT but downregulated in NFL. In contrast, protocadherin gamma subfamily genes were upregulated in DFL and NFL. Quantitative RT-PCR and immunohistochemical studies demonstrated concordant results. Double immunofluorescence studies revealed that CCL20 and CCR6 were co-expressed in both DFL and MALT. We hypothesize that increased expression of CCL20 and MAdCAM-1 and co-expression of CCL20 and CCR6 may play an important role in tumorigenesis.

DOI： 10.1111/cas.12392

Germinal center B-cell-like versus non-germinal center B-cell-like as important prognostic factor for localized nodal DLBCL.

Toshiyuki Habara, Yasuharu Sato, Katsuyoshi Takata, Noriko Iwaki, Hirokazu Okumura, Hiroshi Sonobe, Takehiro Tanaka, Yorihisa Orita, Lamia Abd Al-Kader, Naoko Asano, Daisuke Ennishi, Tadashi Yoshino

Journal of clinical and experimental hematopathology : JCEH 52 ( 2 ) 91 - 9 2012

Language：English Publishing type：Research paper (scientific journal)

Diffuse large B-cell lymphoma (DLBCL) is the most common form of non-Hodgkin's lymphoma. Although many investigations have been performed on the prognostic factors of DLBCL, no reports have focused on localized nodal DLBCL. We examined the prognostic significance of 39 Japanese patients with localized nodal DLBCL with special reference to the germinal center B-cell-like (GCB) versus non-germinal center B-cell-like (NGCB) types. The median age was 65 years with 23 males and 16 females. Using Hans algorithm of immunohistochemistry, 18 patients (46%) exhibited GCB type and 21 (54%) exhibited NGCB type. Twenty-nine patients (74%) presented with disease in the neck (neck group) and 10 (26%) had disease in non-neck regions (non-neck group). Comparing Hans, Choi, and Muris algorithms, patients with GCB type showed statistically significant progression-free survival (PFS) only with Hans algorithm (P = 0.022, P = 0.100, and P = 0.130, respectively). Patient survival analyses revealed that GCB-type patients by Hans algorithm had a better PFS (P = 0.012), and neck-group patients had better PFS and overall survival (OS) (P = 0.018 and P = 0.012, respectively). Univariate analysis revealed that only neck vs. non-neck exhibited a significant difference in terms of OS (P = 0.026). Multivariate analysis revealed that GCB type by Hans algorithm and neck vs. non-neck were significantly different in terms of PFS (P = 0.025 and P = 0.033, respectively). Therefore, the subclassifications of GCB type vs. NGCB type and neck vs. non-neck are important predictive prognostic factors in localized nodal DLBCL.

Association between insulin-like growth factor-1 polymorphisms and stomach cancer risk in a Japanese population. International journal

Daisuke Ennishi, Kohei Shitara, Hidemi Ito, Satoyo Hosono, Miki Watanabe, Seiji Ito, Akira Sawaki, Yasushi Yatabe, Kenji Yamao, Kazuo Tajima, Mitsune Tanimoto, Hideo Tanaka, Nobuyuki Hamajima, Keitaro Matsuo

Cancer science 102 ( 12 ) 2231 - 5 2011.12

Language：English Publishing type：Research paper (scientific journal)

The insulin-like growth factor (IGF) signaling system plays a central role in cellular growth, differentiation and proliferation. Although the association between IGF1 gene polymorphisms and cancer risk has been evaluated for several carcinomas, this association has not yet been examined for stomach cancer. We investigated the association between IGF1 polymorphisms and the risk of stomach cancer in a Japanese population. A total of 703 patients with stomach cancer and 1462 non-cancer control subjects were enrolled in this case-control study. Associations between polymorphisms of 10 IGF1 loci and the risk of stomach cancer were evaluated using odds ratios (OR) and 95% confidence intervals (CI) in multiple logistic regression models. We observed that the C allele in rs1520220 and the G allele in rs4764887 were significantly associated with stomach cancer risk in the per-allele model after adjusting for other risk factors (OR: 1.14 [95% CI: 1.00-1.30] and OR: 1.18 [95% CI: 1.02-1.36], respectively). We also observed a positive and dose-dependent association between the number of risk alleles and stomach cancer risk (P-trend: 0.019) when examining the two loci in the same model. These associations were still seen after adjusting for potential confounders, including sex, age, smoking status, history of diabetes and family history of stomach cancer. We did not find any significant interaction between these factors and the number of risk alleles. In conclusion, we observed a significant association between IGF1 polymorphisms and stomach cancer risk among a Japanese population. Examination of the biological significance of IGF1 is warranted.

DOI： 10.1111/j.1349-7006.2011.02062.x

The utility of positron emission tomography/computed tomography in the staging of extranodal natural killer/T-cell lymphoma. International journal

Hideaki Fujiwara, Yoshinobu Maeda, Yuichiro Nawa, Masayuki Yamakura, Daisuke Ennishi, Yukihiro Miyazaki, Katsuji Shinagawa, Masamichi Hara, Kosei Matsue, Mitsune Tanimoto

European journal of haematology 87 ( 2 ) 123 - 9 2011.8

Language：English Publishing type：Research paper (scientific journal)

Natural killer (NK)/T-cell lymphoma cases are rarely discovered using positron emission tomography/computed tomography (PET/CT). We compared the utility of PET/CT and that of conventional methods (CMs; CT with IV contrast, biopsies from primary sites, and bone marrow examinations) in the staging of extranodal NK/T-cell lymphoma. Nineteen untreated patients with extranodal NK/T-cell lymphoma at three institutions were analyzed. PET/CT and CMs were applied for initial workups following diagnosis. PET/CT and CMs were compared and evaluated for their ability to detect tumor lesions and their influence on the staging and treatment strategies. In total, 116 lesions were detected by CM and PET/CT. Using PET/CT, 108 lesions (93%) were discovered. The number of nodal lesions was 28: all were positive by PET/CT and 26 (93%) by CMs. The number of extranodal lesions was 89: 84 (94%) and 54 (61%) lesions were positive by PET/CT and CMs, respectively. PET/CT was superior to CMs in detecting cutaneous lesions [31/31 lesions (100%) vs. 20/31 lesions (65%), respectively; P=0.042]. Bone marrow involvement was confirmed pathologically in only seven patients; four cases (57%) were positive by PET/CT. Using CMs, ten patients (53%) were stages I-II and nine (47%) were stages III-IV. Using PET/CT, eight patients (42%) were in stages I-II and 11 (58%) were in stages III-IV. PET/CT findings altered the stage and treatment strategy in two cases (11%). Our study demonstrated that PET/CT is a useful tool for detecting extranodal lesions in NK/T-cell lymphoma, particularly cutaneous lesions. PET/CT may therefore influence future staging and treatment strategies.

DOI： 10.1111/j.1600-0609.2011.01645.x

Primary gastrointestinal follicular lymphoma involving the duodenal second portion is a distinct entity: a multicenter, retrospective analysis in Japan. International journal

Katsuyoshi Takata, Hiroyuki Okada, Naoki Ohmiya, Shotaro Nakamura, Yasuhiko Kitadai, Akira Tari, Taiji Akamatsu, Hiroki Kawai, Shu Tanaka, Hiroshi Araki, Takashi Yoshida, Hirokazu Okumura, Hogara Nishisaki, Tamotsu Sagawa, Norihiko Watanabe, Nobuyoshi Arima, Noritaka Takatsu, Masanao Nakamura, Shunichi Yanai, Hiroyasu Kaya, Toshiaki Morito, Yasuharu Sato, Hisataka Moriwaki, Choitsu Sakamoto, Yasumasa Niwa, Hidemi Goto, Tsutomu Chiba, Takayuki Matsumoto, Daisuke Ennishi, Tomohiro Kinoshita, Tadashi Yoshino

Cancer science 102 ( 8 ) 1532 - 6 2011.8

Language：English Publishing type：Research paper (scientific journal)

We conducted a multicenter, retrospective study to determine the anatomical distribution and prognostic factors of gastrointestinal (GI) follicular lymphoma (FL). This study included 125 patients with stage I and II(1) GI-FL. Of the 125 patients, the small intestine was examined in 70 patients, with double-balloon endoscopy and/or capsule endoscopy. The most frequently involved GI-FL site was the duodenal second portion (DSP) (81%), followed by the jejunum (40%); 85% of patients with involvement of the DSP also had jejunal or ileal lesions. The absence of abdominal symptoms and macroscopic appearance of multiple nodules were significantly present in the DSP-positive group. During a median follow up of 40 months, six patients showed disease progression. Patients with involvement of the DSP had better progression-free survival (PFS) than those without such involvement (P = 0.001). A multivariate analysis revealed that male sex, the presence of abdominal symptoms, and negative involvement of the DSP were independently associated with poor PFS. In conclusion, most patients with GI-FL have duodenal lesions associated with multiple jejunal or ileal lesions. Gastrointestinal follicular lymphomas involving the DSP might be a distinct entity showing a favorable clinical course.

DOI： 10.1111/j.1349-7006.2011.01980.x

Allogeneic hematopoietic stem cell transplantation for advanced extranodal natural killer/T-cell lymphoma, nasal type. International journal

Daisuke Ennishi, Yoshinobu Maeda, Nobuharu Fujii, Eisei Kondo, Katsuji Shinagawa, Kazuma Ikeda, Koichi Ichimura, Tadashi Yoshino, Mitsune Tanimoto

Leukemia & lymphoma 52 ( 7 ) 1255 - 61 2011.7

Language：English Publishing type：Research paper (scientific journal)

The prognosis for patients with advanced or refractory extranodal natural killer (NK)/T-cell lymphoma, nasal type (ENKL) is extremely poor. Thus, allogeneic stem cell transplantation (allo-HSCT) should be considered for this disease. However, reports of allo-HSCT for ENKL are limited because of the rarity of the disease. Here, we describe the clinical course of 12 cases of advanced and refractory ENKL treated with allo-HSCT, including five cases with cord blood transplant. With a median follow-up of 13 months (range, 1-168 months), seven patients are alive in remission, five have died, and one treatment-related death occurred. All patients with disease progression at transplant died of disease progression, whereas seven of eight patients with a complete or partial response are long-term survivors. Allo-HSCT is a feasible and promising consolidation therapy for advanced and relapsed ENKL. The disease status before allo-HSCT is well associated with general outcome, and thus induction treatment is very important for this disease.

DOI： 10.3109/10428194.2011.572322

CD5-positive diffuse large B-cell lymphoma: a retrospective study in 337 patients treated by chemotherapy with or without rituximab. International journal

K Miyazaki, M Yamaguchi, R Suzuki, Y Kobayashi, A M Maeshima, N Niitsu, D Ennishi, J-I Tamaru, K Ishizawa, M Kashimura, Y Kagami, K Sunami, H Yamane, M Nishikori, H Kosugi, T Yujiri, R Hyo, N Katayama, T Kinoshita, S Nakamura

Annals of oncology : official journal of the European Society for Medical Oncology 22 ( 7 ) 1601 - 1607 2011.7

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: CD5-positive (CD5+) diffuse large B-cell lymphoma (DLBCL) shows poor prognosis and frequent central nervous system (CNS) relapses under anthracycline-containing chemotherapy. The aim of this study was to determine the prognosis and CNS relapse incidence of CD5+ DLBCL in the rituximab era. PATIENTS AND METHODS: We analyzed 337 patients with CD5+ DLBCL who received chemotherapy with (R-chemotherapy group; n = 184) or without (chemotherapy group; n = 153) rituximab. RESULTS: No significant difference was found in clinical background comparisons between the two groups. In the R-chemotherapy group, 60% of the patients were older than 65 years at diagnosis. Both the complete response rate and overall survival (OS) were significantly better in the R-chemotherapy group (P = 0.0003 and P = 0.002, respectively). Multivariate analysis confirmed that chemotherapy without rituximab was associated with unfavorable OS. However, the probability of CNS relapse did not differ between the two groups (P = 0.89). The CNS relapse was strongly associated with short OS (P < 0.0001). In the R-chemotherapy group, 83% of patients who experienced CNS relapse had parenchymal disease. CONCLUSIONS: Our results indicate that rituximab improves the OS of patients with CD5+ DLBCL but does not decrease the CNS relapse rate. More effective treatments with CNS prophylaxis are needed for CD5+ DLBCL patients.

DOI： 10.1093/annonc/mdq627

Hepatic toxicity and prognosis in hepatitis C virus-infected patients with diffuse large B-cell lymphoma treated with rituximab-containing chemotherapy regimens: a Japanese multicenter analysis. International journal

Daisuke Ennishi, Yoshinobu Maeda, Nozomi Niitsu, Minoru Kojima, Koji Izutsu, Jun Takizawa, Shigeru Kusumoto, Masataka Okamoto, Masahiro Yokoyama, Yasushi Takamatsu, Kazutaka Sunami, Akira Miyata, Kayoko Murayama, Akira Sakai, Morio Matsumoto, Katsuji Shinagawa, Akinobu Takaki, Keitaro Matsuo, Tomohiro Kinoshita, Mitsune Tanimoto

Blood 116 ( 24 ) 5119 - 25 2010.12

Language：English Publishing type：Research paper (scientific journal)

The influence of hepatitis C virus (HCV) infection on prognosis and hepatic toxicity in patients with diffuse large B-cell lymphoma in the rituximab era is unclear. Thus, we analyzed 553 patients, 131 of whom were HCV-positive and 422 of whom were HCV-negative, with DLBCL treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (RCHOP)-like chemotherapy. Survival outcomes and hepatic toxicity were compared according to HCV infection. The median follow-up was 31 and 32 months for patients who were HCV-positive and HCV-negative, respectively. HCV infection was not a significant risk factor for prognosis (3-year progression-free survival, 69% vs 77%, P = .22; overall survival, 75% vs 84%, P = .07). Of 131 patients who were HCV-positive, 36 (27%) had severe hepatic toxicity (grade 3-4), compared with 13 of 422 (3%) patients who were HCV-negative. Multivariate analysis revealed that HCV infection was a significant risk factor for severe hepatic toxicity (hazard ratio: 14.72; 95% confidence interval, 6.37-34.03; P < .001). An exploratory analysis revealed that pretreatment transaminase was predictive of severe hepatic toxicity. HCV-RNA levels significantly increased during immunochemotherapy (P = .006). These results suggest that careful monitoring of hepatic function and viral load is indicated during immunochemotherapy for HCV-positive patients.

DOI： 10.1182/blood-2010-06-289231

Cancer of unknown primary site: a review of 28 cases and the efficacy of cisplatin/docetaxel therapy at a single institute in Japan.

Hisakazu Nishimori, Shunji Takahashi, Katsuyuki Kiura, Daisuke Ennishi, Takayuki Kobayashi, Koji Sano, Eiji Shinozaki, Masahiro Yokoyama, Yuko Mishima, Yasuhito Terui, Keisho Chin, Nobuyuki Mizunuma, Yoshinori Ito, Seiichiro Nishimura, Kengo Takeuchi, Yuichi Ishikawa, Masahiko Oguchi, Mitsune Tanimoto, Kiyohiko Hatake

Acta medica Okayama 64 ( 5 ) 285 - 91 2010.10

Language：English Publishing type：Research paper (scientific journal)

We evaluated the efficacy and toxicity of cisplatin/docetaxel (CDDP/TXT) chemotherapy and identified prognostic factors in Japanese patients with cancer of unknown primary site (CUP). Twenty-eight consecutive patients seen at a single institute were reviewed retrospectively. Sixteen patients were treated with TXT 80 mg/m2, followed by CDDP 75 mg/m2. The overall response rate to CDDP/TXT treatment was 62.5%, with a median survival time (MST) of 22.7 months. Common adverse reactions were myelosuppression and hyponatremia. The MST of all 28 patients with CUP was 8.3 months, and the 1-year overall survival rate was 45.6%. Univariate analysis identified 5 prognostic factors:performance status, liver involvement, bone involvement, pleural involvement, and lymph node involvement. In conclusion, CDDP/TXT chemotherapy is effective with tolerable toxicity in patients with CUP. Japanese patients with CUP might be chemosensitive and may survive longer.

Is statin use really associated with efficacy of rituximab? International journal

Hiroaki Asai, Masahiro Yokoyama, Yasuhito Terui, Daisuke Ennishi, Kengo Takeuchi, Kiyohiko Hatake

Journal of clinical oncology : official journal of the American Society of Clinical Oncology 28 ( 24 ) e424-5; author reply e427-8 2010.8

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