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O-02 p21 LOSS INDUCES AN INFLAMMATORY SKIN DISEASE AND SPONTANEOUS TU- MOR DEVELOPMENT IN MICE BEARING EPIDERMAL SPECIFIC pRb ABLATION SAIZ-LADERA C 1 , LARA MF, GARÍN M 1 , RUIZ S, SANTOS M 1 , LORZ C 1 , GARCIA ESCUDERO R 1 , BRAVO A 2 , FERNANDEZ-CAPETILLO O 3 , SEGRELLES C 1 PARAMIO J 1 1 CENTRO DE INVESTIGACIONES ENERGÉTICAS, MEDIOAMBIENTALES Y TECNOLÓGICAS (CIEMAT), MADRID (RD06/0020/0029) 2 FACULTAD DE VETERINARIA, USC 3 CENTRO NACIONAL DE INVESTIGACIONES ONCOLÓGICAS (CNIO), MADRID The ablation of the retinoblastoma gene product in epidermis results in hyperplasia and hyperkeratosis, due to increased proliferation and altered differentiation, but not to sporadic tumors. Given the wide functions of p21 in epidermis and the fact that p21 can control proliferation and differentiation, even in the absence of pRb, we have now generated mice doubly deficient in pRb and p21 (pRb Epi p21-/-). In these mice, we found that p21 compensates for some of the effects observed in the absence of pRb, as the phenotypic abnormalities of Rb-deficient epidermis become more severe with the consecutive loss of Cdkn1a alleles. In addition, we also observed the development of an inflammatory phenotype and the spontaneous development of tumors of epithelial origin, in particular affecting oral tissues. Gene profiling studies in conjunction with biochemical analyses revealed changes affecting p53 and DNA damage response in pRb Epi p21-/- mouse skin, and identified a significant overlap between deregulated genes in mouse and human squamous cancers. Our findings support a model in which pRb, in conjunction with p21, plays a central role in regulating multiple epithelial processes leading to specific tumor suppressor functions. O-03 DOWN-REGULATION OF FOXP1 IS REQUIRED DURING GERMINAL CENTER B CELL FUNCTION SAGARDOY A 1 , MARTÍNEZ-FERRANDIS J 1,2 , ROA S 1 , BUNTING K 2 , AZNAR A 1 , ELEMENTO O 2 , SHAKNOVICH R 2 , FONTÁN L 1 , FRESQUET V 1 , ROBLES EF 1 , SAGAERT X 3 , MELNICK A 2 , MARTÍNEZ- CLIMENT JA 1 1 CENTRO DE INVESTIGACIÓN MÉDICA APLICADA (CIMA),PAMPLONA (RD06/0020/0088) 2 WEILL CORNELL MEDICAL COLLEGE NY (USA) 3 UNIVERSITY OF LEUVEN, BEGIUM B cell maturation, germinal center (GC) formation and terminal differentiation are dependent on the interplay between BCL6 and other key transcriptional regulators. Forkhead box protein 1 (FOXP1) is a transcription factor that coordinates transitions between differentiation stages at early B cell development. FOXP1 expression has been associated with poor prognosis in patients with diffuse large B cell lymphoma (DLBCL), but whether it plays a role in mature B cells is unknown. Analyses of human tonsilar B cell subpopulations helped us to reveal that FOXP1 shows opposite expression pattern to BCL6, suggesting that FOXP1 may play a role during late B cell development in the course of B cell activation and GC formation. Chromatin immunoprecipitation and gene expression assays on human tonsilar samples and DLBCL cells indicated that FOXP1 may act as both a transcriptional activator and repressor of a network of genes typically involved in the GC reaction, half of which are also BCL6 targets. To study FOXP1 function in vivo, we developed transgenic mice expressing human FOXP1 in the lymphoid lineage. These mice exhibited irregular expansion of GCs in the spleen, showing a moderate increase in naïve (B220 + IgM hi IgM hi/lo ) and marginal-zone B cells (B220 + CD21 + CD23 - ) that was accompanied by a significant decrease in GC B cells (B220 + Fas + PNA hi /GL7 hi ). Furthermore, aberrant expression of FOXP1 impaired the transcription of non-coding 1 germline transcripts (GLTs) and inhibited efficient class-switching to the IgG1 isotype. Taken together, these studies reveal that FOXP1 is physiologically down-regulated in GC B cells and that aberrant expression of FOXP1 may impair the mechanisms triggered by B cell activation, potentially antagonizing some of the actions of BCL6 during the regulation of the GC reaction. 18 19
O-04 EPIGENETIC PROFILE IN CHRONIC LYMPHOCYTIC LEUKEMIA USING METHYLA- TION-SPECIFIC MULTIPLEX LIGATION-DEPENDENT PROBE AMPLIFICATION COSIALLS AM 1 , SANTIDRIÁN AF 1 , COLL-MULET LL 1 , IGLESIAS-SERRET D 1 , GONZÁLEZ-GIRONÈS DM 1 , PÉREZ-PERARNAU A 1 , RUBIO-PATIÑO C 1 , GONZÁLEZ-BARCA E 2 , ALONSO E 3 , PONS G 1 , GIL J 1 1 DEPARTAMENT DE CIÈNCIES FISIOLÒGIQUES II, INSTITUT D’INVESTIGACIÓ BIOMÈDICA DE BELL- VITGE (IDIBELL)-UNIVERSITAT DE BARCELONA, L’HOSPITALET DE LLOBREGAT, BARCELONA, SPAIN (RD06/0020/0097) 2 DEPARTAMENT D’HEMATOLOGIA CLÍNICA, IDIBELL-INSTITUT CATALÀ D’ONCOLOGIA, L’HOSPITALET DE LLOBREGAT, BARCELONA, SPAIN (RD06/0020/1040) 3 SERVEI D’HEMATOLOGIA, IDIBELL-HOSPITAL DE BELLVITGE, L’HOSPITALET DE LLOBREGAT, BAR- CELONA, SPAIN Aims: The contribution of epigenetic silencing mechanisms in the pathogenesis of chronic lymphocytic leukemia (CLL) has gained importance in recent years. However, the methods used so far are labor intensive which makes it difficult to implement the methylation status assessment in clinical practice. Here we analyze the methylation status of 35 tumor suppressor genes using methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) in CLL. Materials & Methods: DNA of 37 samples from patients with CLL, 6 healthy donors and Jurkat and Ramos cells lines was analyzed by MS-MLPA. Results: Our results confirm that hypermethylation is a common and not randomly distributed event in CLL, and some genes like WT1, CDH13, IGSF4/TSLC1, GATA5, DAPK1 or RARB are hypermethylated in more than 25% of the analyzed samples. Importantly, MS- MLPA also detected hypermethylation of some genes not reported previously in CLL, and their methylation status was confirmed by bisulfite sequencing. Conclusions: These results indicate that MS-MLPA is a useful technique for the detection of methylation in CLL samples with automated data processing at a low cost per sample. Selecting CLL-specific methylation targets in order to generate a CLL-specific MS-MLPA probe set could enhance its usefulness as a tool in studies of risk stratification and guiding the best therapeutic decision. Observaciones: Este trabajo se ha realizado en colaboración entre los grupos de la RTICC del Dr. Joan Gil Santano y la Dra. Eva María González Barca (códigos de grupo RD06/0020/0097 y RD06/0020/1040). O-05 CRYPTIC DUPLICATIONS AND DELETIONS TO IMPROVE RISK GROUPS IN CHILD- HOOD ACUTE LYMPHOBLASTIC LEUKEMIA LÓPEZ-LÓPEZ E 1 , PUIGGROS A 2 , PIÑAN MA 3 , NAVAJAS A 4 , SOLÉ F 2 , GARCÍA-ORAD A 1 1 DEPARTMENT OF GENETICS, PHYSIC ANTHROPOLOGY AND ANIMAL PHYSIOLOGY, UNIVERSITY OF THE BASQUE COUNTRY, BILBAO (RD06/0020/0048) 2 GROUP OF TRANSLATIONAL RESEARCH IN HEMATOLOGIC NEOPLASIAS, IMIM HOSPITAL DEL MAR, BARCELONA (RD07/0020/2004) 3 DEPARTMENT OF HEMATOLOGY AND HEMOTHERAPY, UNIVERSITY HOSPITAL CRUCES, BILBAO (RD06/0020/0048) 4 DEPARTMENT OF ONCOHEMATOLOGY, UNIVERSITY HOSPITAL CRUCES, BILBAO (RD06/0020/0048) Acute lymphoblastic leukemia (B-ALL) is the most common pediatric malignancy and a major cause of death by disease in children. Survival has increased adapting therapy to risk groups, characterized by prognostic markers that include cytogenetic alterations. Therapy is intensified in higher risk patients. However, some patients do not respond properly to treatment and have to be moved to higher risk groups. This could mean that the risk groups are not well defined, due in part to undetected cryptic alterations. Therefore, in this study we wanted to identify novel cryptic deletions and duplications that could allow the recognition of the patients that may be receiving less treatment than they need. Methods We analyzed DNA samples from 23 patients diagnosed with B-ALL from the different risk groups (7 standard risk, 10 high risk, 1 very high risk, and 5 that changed risk). We used the Cytogenetics Whole-Genome 2.7M platform (Affymetrix) and Chromosome Analysis Suite program. Results Some recurrent aberrations were present in patients from different risk groups and may be associated with the leukemic process (deletions at 1q42.3, 3q13.2, 3q26.3, 3p14.2, 7q34, 8q12.1, 9p21.3, 12p13.2, 14q11.2, 17q21.3, 22q11.2). Interestingly, we detected new recurrent aberrations that distinguish the standard risk (7p14.1 and 14q24.2 deletions) and high risk patients (12q23.1 deletion). We also detected alterations (1q21.3 and 1q25.1 duplication, 5q33.3 alteration, 10q25.1-q25.2 and 12q12 deletion) that distinguish standardrisk patients who remain in this group from those who were changed to high-risk. These alterations could be used to improve risk groups classification and treatment individualization. Conclusions Risk groups classification could be improved in patients with pediatric B-ALL through the analysis of new cryptic deletions and duplications.This project was supported by RETICS (RD/06/0020/0048), Basque Government (GIC10/71, SAI10/03 and 2006111015) and UPV/ EHU (UFI11/35). Support by SGIker (UPV/EHU) is gratefully acknowledged. 20 21
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Page 26 and 27: P-07 DIOXIN RECEPTOR KNOCK-DOWN PRO
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Page 38 and 39: P-30 GENETIC VARIANTS IN MIRNAS: NE
Page 40 and 41: P-34 CARACTERIZACIÓN CLÍNICA Y BI
Page 42 and 43: P-37 IDENTIFICATION OF PROTEIN BIOM
Page 44 and 45: P-41 LA FOSFORILACIÓN DE eIF4E AUM
Page 46: P-45 METHODS FOR RNA AND miRNA PURI
Page 49 and 50: Apellidos Nombre E-mail Grupo RTICC

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