Gesk, S. (Stefan)
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- Deregulation of the telomerase reverse transcriptase (TERT) gene by chromosomal translocations in B-cell malignancies(American Society of Hematology, 2010) Gascoyne, R.D (R. D.); Tönnies, H. (Holger); Ammerpohl, O. (Ole); Dyer, M.J.S. (Martin J. S.); Martinez-Climent, J.A. (José Ángel); Nagel, I. (Inga); Akasaka, T. (T.); Horsman, D. (D.); Gesk, S. (Stefan); Harder, L. (Lana); Klapper, W. (Wolfram); Callet-Bauchu, E. (E.); Siebert, R. (Reiner); Szczepanowski, M. (Monika); Stilgenbauer, S. (Stepahn); Majid, A. (Aneela); Martin-Subero, J.I. (Jose Ignacio)Sequence variants at the TERT-CLPTM1L locus in chromosome 5p have been recently associated with disposition for various cancers. Here we show that this locus including the gene encoding the telomerase reverse-transcriptase TERT at 5p13.33 is rarely but recurrently targeted by somatic chromosomal translocations to IGH and non-IG loci in B-cell neoplasms, including acute lymphoblastic leukemia, chronic lymphocytic leukemia, mantle cell lymphoma and splenic marginal zone lymphoma. In addition, cases with genomic amplification of TERT locus were identified. Tumors bearing chromosomal aberrations involving TERT showed higher TERT transcriptional expression and increased telomerase activity. These data suggest that deregulation of TERT gene by chromosomal abnormalities leading to increased telomerase activity might contribute to B-cell lymphomagenesis.
- GeneChip analyses point to novel pathogenetic mechanisms in mantle cell lymphoma(Wiley-Blackwell, 2009) Krause, K. (Kristina); Dreyling, M. (Martin); Hasenclever, D. (D.); Kreuz, M. (Markus); Dyer, M.J.S. (Martin J. S.); Berger, H. (H.); Arnold, N. (Norbert); Martinez-Climent, J.A. (José Ángel); Wagner, F. (Florian); Gesk, S. (Stefan); Harder, L. (Lana); Klapper, W. (Wolfram); Zamo, A. (Alberto); Siebert, R. (Reiner); Vater, I. (Inga); Potter, K. (Kathleen N.); Martin-Subero, J.I. (Jose Ignacio)The translocation t(11;14)(q13;q32) is the genetic hallmark of mantle cell lymphoma (MCL) but is not sufficient for inducing lymphomagenesis. Here we performed genome-wide 100K GeneChip Mapping in 26 t(11;14)-positive MCL and six MCL cell lines. Partial uniparental disomy (pUPD) was shown to be a recurrent chromosomal event not only in MCL cell lines but also in primary MCL. Remarkably, pUPD affected recurrent targets of deletion like 11q, 13q and 17p. Moreover, we identified 12 novel regions of recurrent gain and loss as well as 12 high-level amplifications and eight homozygously deleted regions hitherto undescribed in MCL. Interestingly, GeneChip analyses identified different genes, encoding proteins involved in microtubule dynamics, such as MAP2, MAP6 and TP53, as targets for chromosomal aberration in MCL. Further investigation, including mutation analyses, fluorescence in situ hybridisation as well as epigenetic and expression studies, revealed additional aberrations frequently affecting these genes. In total, 19 of 20 MCL cases, which were subjected to genetic and epigenetic analyses, and five of six MCL cell lines harboured at least one aberration in MAP2, MAP6 or TP53. These findings provide evidence that alterations of microtubule dynamics might be one of the critical events in MCL lymphomagenesis contributing to chromosomal instability.
- A cyclin-D1 interaction with BAX underlies its oncogenic role and potential as a therapeutic target in mantle cell lymphoma(National Academy of Sciences, 2011-07-26) Fresquet, V. (Vicente); Beltran, E. (E.); Rieger, M. (Melissa); Lossos, I.S. (Izidore S.); Martinez-Climent, J.A. (José Ángel); Montes-Moreno, S. (Santiago); Gesk, S. (Stefan); Almada, L.L. (Luciana L.); Richter, J.A. (José Ángel); Raquel; Siebert, R. (Reiner); Sagardoy, A. (Ainara); Martinez-Useros, J. (Javier); Fernandez-Zapico, M.E. (Martín E.); Prosper-Cardoso, F. (Felipe); Calasanz-Abinzano, M.J. (Maria Jose); Piris, M.A. (Miguel A.); Sesma, I. (Izaskun)The chromosomal translocation t(11;14)(q13;q32) leading to cyclin-D1 overexpression plays an essential role in the development of mantle cell lymphoma (MCL), an aggressive tumor that remains incurable with current treatment strategies. Cyclin-D1 has been postulated as an effective therapeutic target, but the evaluation of this target has been hampered by our incomplete understanding of its oncogenic functions and by the lack of valid MCL murine models. To address these issues, we generated a cyclin-D1-driven mouse model in which cyclin-D1 expression can be regulated externally. These mice developed cyclin-D1-expressing lymphomas capable of recapitulating features of human MCL. We found that cyclin-D1 inactivation was not sufficient to induce lymphoma regression in vivo; however, using a combination of in vitro and in vivo assays, we identified a novel prosurvival cyclin-D1 function in MCL cells. Specifically, we found that cyclin-D1, besides increasing cell proliferation through deregulation of the cell cycle at the G(1)-S transition, sequestrates the proapoptotic protein BAX in the cytoplasm, thereby favoring BCL2's antiapoptotic function. Accordingly, cyclin-D1 inhibition sensitized the lymphoma cells to apoptosis through BAX release. Thus, genetic or pharmacologic targeting of cyclin-D1 combined with a proapoptotic BH3 mimetic synergistically killed the cyclin-D1-expressing murine lymphomas, human MCL cell lines, and primary lymphoma cells. Our study identifies a role of cyclin-D1 in deregulating apoptosis in MCL cells, and highlights the potential benefit of simultaneously targeting cyclin-D1 and survival pathways in patients with MCL. This effective combination therapy also might be exploited in other cyclin-D1-expressing tumors.
- A Comprehensive Microarray-Based DNA Methylation Study of 367 Hematological Neoplasms(Public Library of Science, 2009) Cigudosa, J.C. (Juan Cruz); Stein, H. (Harald); Ammerpohl, O. (Ole); Dreyling, M. (Martin); Richter, J. (Julia); Trümper, L. (Lorenz); Montesinos-Rongen, M. (Manuel); Roman-Gomez, J. (José); Dyer, M.J.S. (Martin J. S.); Alvarez, S. (Sara); Bug, S. (Stefanie); Dürig, J. (Jan); Nagel, I. (Inga); Seifert, M. (Marc); Gesk, S. (Stefan); Bibikova, M. (Marina); Küppers, R. (Ralf); Harder, L. (Lana); Klapper, W. (Wolfram); Brüggemann, M. (Monika); Siebert, R. (Reiner); Vater, I. (Inga); Haferlach, C. (Claudia); Deckert, M. (Martina); Wickham, E. (Eliza); Du, M.Q. (Ming Q.); Hansmann, M.L. (Martin-Leo); Potter, K. (Kathleen N.); Prosper-Cardoso, F. (Felipe); Fan, J.B. (Jian-Bing); Calasanz-Abinzano, M.J. (Maria Jose); Hartmann, S. (Sylvia); Aguirre-Ena, X. (Xabier); Martin-Subero, J.I. (Jose Ignacio); Suela, J. (Javier)Background: Alterations in the DNA methylation pattern are a hallmark of leukemias and lymphomas. However, most epigenetic studies in hematologic neoplasms (HNs) have focused either on the analysis of few candidate genes or many genes and few HN entities, and comprehensive studies are required. Methodology/Principal Findings: Here, we report for the first time a microarray-based DNA methylation study of 767 genes in 367 HNs diagnosed with 16 of the most representative B-cell (n = 203), T-cell (n = 30), and myeloid (n = 134) neoplasias, as well as 37 samples from different cell types of the hematopoietic system. Using appropriate controls of B-, T-, or myeloid cellular origin, we identified a total of 220 genes hypermethylated in at least one HN entity. In general, promoter hypermethylation was more frequent in lymphoid malignancies than in myeloid malignancies, being germinal center mature B-cell lymphomas as well as B and T precursor lymphoid neoplasias those entities with highest frequency of geneassociated DNA hypermethylation. We also observed a significant correlation between the number of hypermethylated and hypomethylated genes in several mature B-cell neoplasias, but not in precursor B- and T-cell leukemias. Most of the genes becoming hypermethylated contained promoters with high CpG content, and a significant fraction of them are targets of the polycomb repressor complex. Interestingly, T-cell prolymphocytic leukemias show low levels of DNA hypermethylation and a comparatively large number of hypomethylated genes, many of them showing an increased gene expression. Conclusions/Significance: We have characterized the DNA methylation profile of a wide range of different HNs entities. As well as identifying genes showing aberrant DNA methylation in certain HN subtypes, we also detected six genes—DBC1, DIO3, FZD9, HS3ST2, MOS, and MYOD1—that were significantly hypermethylated in B-cell, T-cell, and myeloid malignancies. These might therefore play an important role in the development of different HNs.
- Characterization of 8p21.3 chromosomal deletions in B-cell lymphoma: TRAIL-R1 and TRAIL-R2 as candidate dosage-dependent tumor suppressor genes(American Society of Hematology, 2005) Benito-Boilos, A. (Alberto); DeLeeuw, R. (R.); Dyer, M.J.S. (Martin J. S.); Rosenwald, A. (Andreas); Pinkel, D. (Daniel); Karran, E.L. (E. L.); Martinez-Climent, J.A. (José Ángel); Blesa, D. (David); Gesk, S. (Stefan); Fernandez-Luna, J.L. (J.L.); Balasas, T. (T.); Siebert, R. (Reiner); Mestre-Escorihuela, C. (Cinta); Esteller, M. (Manel); Staudt, L.M. (Louis M.); Rubio-Moscardo, F. (Fanny); Climent, J. (Javier); Schilhabel, M. (Markus); Martinez, J.I. (José I.)Deletions of chromosome 8p are a recurrent event in B-cell non-Hodgkin lymphoma (B-NHL), suggesting the presence of a tumor suppressor gene. We have characterized these deletions using comparative genomic hybridization to microarrays, fluorescence in situ hybridization (FISH) mapping, DNA sequencing, and functional studies. A minimal deleted region (MDR) of 600 kb was defined in chromosome 8p21.3, with one mantle cell lymphoma cell line (Z138) exhibiting monoallelic deletion of 650 kb. The MDR extended from bacterial artificial chromosome (BAC) clones RP11-382J24 and RP11-109B10 and included the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptor gene loci. Sequence analysis of the individual expressed genes within the MDR and DNA sequencing of the entire MDR in Z138 did not reveal any mutation. Gene expression analysis and quantitative reverse transcriptase-polymerase chain reaction (QRT-PCR) showed down-regulation of TRAIL-R1 and TRAIL-R2 receptor genes as a consistent event in B-NHL with 8p21.3 loss. Epigenetic inactivation was excluded via promoter methylation analysis. In vitro studies showed that TRAIL-induced apoptosis was dependent on TRAIL-R1 and/or -R2 dosage in most tumors. Resistance to apoptosis of cell lines with 8p21.3 deletion was reversed by restoration of TRAIL-R1 or TRAIL-R2 expression by gene transfection. Our data suggest that TRAIL-R1 and TRAIL-R2 act as dosage-dependent tumor suppressor genes whose monoallelic deletion can impair TRAIL-induced apoptosis in B-cell lymphoma.
- Biallelic inactivation of TRAF3 in a subset of B-cell lymphomas with interstitial del(14)(q24.1q32.33)(Nature Publishing Group, 2009) Tönnies, H. (Holger); Ammerpohl, O. (Ole); Richter, J. (Julia); Dyer, M.J.S. (Martin J. S.); Bastard, C. (C.); Bug, S. (Stefanie); Martinez-Climent, J.A. (José Ángel); Nagel, I. (Inga); Gesk, S. (Stefan); Harder, L. (Lana); Callet-Bauchu, E. (E.); Siebert, R. (Reiner); Vater, I. (Inga); Schroers, E. (E.); Calasanz-Abinzano, M.J. (Maria Jose); Salido, M. (Marta); Majid, A. (Aneela); Martin-Subero, J.I. (Jose Ignacio)