Cigudosa, J.C. (Juan Cruz)

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    Epigenetic Signatures Associated with Different Levels of Differentiation Potential in Human Stem Cells
    (Public Library of Science, 2009) Cigudosa, J.C. (Juan Cruz); Roman-Gomez, J. (José); Ballestar, E. (E.); Aranda, P. (P.); Prieto, I. (Inés); Andreu, E.J. (Enrique José); Siebert, R. (Reiner); Esteller, M. (Manel); Prosper-Cardoso, F. (Felipe); Aguirre-Ena, X. (Xabier); Martin-Subero, J.I. (Jose Ignacio)
    The therapeutic use of multipotent stem cells depends on their differentiation potential, which has been shown to be variable for different populations. These differences are likely to be the result of key changes in their epigenetic profiles.
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    Chromosomal abnormalities clustering in multiple myeloma reveals cytogenetic subgroups with nonrandom acquisition of chromosomal changes
    (Nature Publishing Group, 2004) Cigudosa, J.C. (Juan Cruz); Guillen-Grima, F. (Francisco); Harder, L. (Lana); Siebert, R. (Reiner); Prosper-Cardoso, F. (Felipe); Calasanz-Abinzano, M.J. (Maria Jose); Odero, M.D. (Maria Dolores); Martin-Subero, J.I. (Jose Ignacio); Saez, B. (Borja)
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    Preclinical activity of LBH589 alone or in combination with chemotherapy in a xenogeneic mouse model of human acute lymphoblastic leukemia.
    (Nature Publishing Group, 2012) Vilas, A. (Amaia); Cigudosa, J.C. (Juan Cruz); Roman-Gomez, J. (José); San-Jose-Eneriz, E. (Edurne); Blanco-Prieto, M.J. (María José); Garate, L. (Leire); Martinez-Climent, J.A. (José Ángel); Rifon, J. J. (Jose J.); Ribera, J.M. (José María); Miranda, E. (Estibaliz); Martino-Rodriguez, A. (Alba) de; Garcia-de-Jalon, J.A. (José A.); Prosper-Cardoso, F. (Felipe); Rio, P. (Paula); Segura, V. (Víctor); Calasanz-Abinzano, M.J. (Maria Jose); Aguirre-Ena, X. (Xabier); Abizanda-Sarasa, G. (Gloria); Martin-Subero, J.I. (Jose Ignacio); Moreno, C. (Cristina)
    Histone deacetylases (HDACs) have been identified as therapeutic targets due to their regulatory function in chromatin structure and organization. Here, we analyzed the therapeutic effect of LBH589, a class I-II HDAC inhibitor, in acute lymphoblastic leukemia (ALL). In vitro, LBH589 induced dose-dependent antiproliferative and apoptotic effects, which were associated with increased H3 and H4 histone acetylation. Intravenous administration of LBH589 in immunodeficient BALB/c-RAG2(-/-)γc(-/-) mice in which human-derived T and B-ALL cell lines were injected induced a significant reduction in tumor growth. Using primary ALL cells, a xenograft model of human leukemia in BALB/c-RAG2(-/-)γc(-/-) mice was established, allowing continuous passages of transplanted cells to several mouse generations. Treatment of mice engrafted with T or B-ALL cells with LBH589 induced an in vivo increase in the acetylation of H3 and H4, which was accompanied with prolonged survival of LBH589-treated mice in comparison with those receiving vincristine and dexamethasone. Notably, the therapeutic efficacy of LBH589 was significantly enhanced in combination with vincristine and dexamethasone. Our results show the therapeutic activity of LBH589 in combination with standard chemotherapy in pre-clinical models of ALL and suggest that this combination may be of clinical value in the treatment of patients with ALL.
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    DNA Methylation Profiles and Their Relationship with Cytogenetic Status in Adult Acute Myeloid Leukemia
    (Public Library of Science, 2010) Fernandez, A. (Agustín); Cervera, J. (Jose); Cigudosa, J.C. (Juan Cruz); Acquadro, F. (Francesco); Roman-Gomez, J. (José); Wunderlich, M. (Mark); Alvarez, S. (Sara); Mulloy, J.C. (James C.); Rodriguez-Perales, S. (Sandra); Valencia, A. (Ana); Siebert, R. (Reiner); Sanz, M.A. (Miguel A.); Esteller, M. (Manel); Maiques, A. (Alba); Prosper-Cardoso, F. (Felipe); Calasanz-Abinzano, M.J. (Maria Jose); Aguirre-Ena, X. (Xabier); Martin-Subero, J.I. (Jose Ignacio); Suela, J. (Javier)
    Background: Aberrant promoter DNA methylation has been shown to play a role in acute myeloid leukemia (AML) pathophysiology. However, further studies to discuss the prognostic value and the relationship of the epigenetic signatures with defined genomic rearrangements in acute myeloid leukemia are required. Methodology/Principal Findings: We carried out high-throughput methylation profiling on 116 de novo AML cases and we validated the significant biomarkers in an independent cohort of 244 AML cases. Methylation signatures were associated with the presence of a specific cytogenetic status. In normal karyotype cases, aberrant methylation of the promoter of DBC1 was validated as a predictor of the disease-free and overall survival. Furthermore, DBC1 expression was significantly silenced in the aberrantly methylated samples. Patients with chromosome rearrangements showed distinct methylation signatures. To establish the role of fusion proteins in the epigenetic profiles, 20 additional samples of human hematopoietic stem/ progenitor cells (HSPC) transduced with common fusion genes were studied and compared with patient samples carrying the same rearrangements. The presence of MLL rearrangements in HSPC induced the methylation profile observed in the MLL-positive primary samples. In contrast, fusion genes such as AML1/ETO or CBFB/MYH11 failed to reproduce the epigenetic signature observed in the patients. Conclusions/Significance: Our study provides a comprehensive epigenetic profiling of AML, identifies new clinical markers for cases with a normal karyotype, and reveals relevant biological information related to the role of fusion proteins on the methylation signature
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    Identification of recurrent chromosomal breakpoints in multiple myeloma with complex karyotypes by combined G-banding, spectral karyotyping, and fluorescence in situ hybridization analyses
    (Elsevier, 2006) Cigudosa, J.C. (Juan Cruz); Largo, C. (Cristina); Siebert, R. (Reiner); Prosper-Cardoso, F. (Felipe); Calasanz-Abinzano, M.J. (Maria Jose); Martin, M.C. (María C.); Odero, M.D. (Maria Dolores); Martin-Subero, J.I. (Jose Ignacio); Saez, B. (Borja)
    The description of novel chromosomal aberrations in multiple myeloma (MM) remains necessary to fully understand the pathogenesis of this heterogeneous disease. Therefore, we have used spectral karyotyping (SKY) and fluorescence in situ hybridization (FISH) with locus-specific probes to characterize the chromosomal abnormalities in 11 MM cases in which G-banding revealed a complex karyotype. SKY refined G-banding karyotypes in all cases. Recurrent breakpoints involved bands Xp11, 8q24, 11q13, 12q13, 13q21, and 14q32. In addition, combined SKY and FISH analyses permitted us to identify a subset of patients harboring 22q11.2 rearrangements not involving the IGL locus. This finding suggests the presence of other gene(s) in band 22q11 that might be implicated in MM pathogenesis. Moreover, band 1p13 was identified as a novel partner of immunoglobulin (IG) translocations in MM. Finally, using interphase FISH, we have detected interstitial deletions in 13q14 and 17p13, as well as cryptic translocations affecting IGH, which were neither detected by G-banding nor by SKY. The results of the present study suggest the existence of hitherto unknown nonrandom chromosomal changes that may play a role in the pathogenesis of MM. Our findings underline the importance of the combination of banding, SKY, and FISH analyses to increase the accuracy of karyotype interpretation in plasma cell neoplasias.
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    Interphase FISH for the detection of breakpoints in IG loci and chromosomal changes with adverse prognostic impact in multiple myeloma with normal karyotypes
    (Elsevier, 2006) Cigudosa, J.C. (Juan Cruz); Siebert, R. (Reiner); Hernandez, R. (Roberto); Prosper-Cardoso, F. (Felipe); Calasanz-Abinzano, M.J. (Maria Jose); Odero, M.D. (Maria Dolores); Martin-Subero, J.I. (Jose Ignacio); Saez, B. (Borja)
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    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.
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    Spanish guidelines for the use of targeted deep sequencing in myelodysplastic syndromes and chronic myelomonocytic leukaemia
    (2019) Cedena, M.T. (María Teresa); Zamora, L. (Lurdes); Cervera, J. (Jose); Cigudosa, J.C. (Juan Cruz); Fernandez-Mercado, M. (Marta); Palomo, L. (Laura); Alvarez, S. (Sara); Sole, F. (Francesc); Hernandez, J.M. (J. M.); Ibáñez, M. (Mariam); Acha, P. (Pamela); Such, E. (Esperanza); Tazón-Vega, Bárbara; Valcarcel, D. (David); Benito, R. (Rocío); Rapado, I. (Inmaculada); Cabezón, Marta; Vazquez, I. (Iria); Hernandez-Rivas, J.M. (Jesús M.); Larrayoz, M.J. (María J.); Fuster-Tormo, F. (Francisco); Calasanz-Abinzano, M.J. (Maria Jose); Sanz, G. (Guillermo); Abaigar, M. (María)
    The landscape of medical sequencing has rapidly changed with the evolution of next generation sequencing (NGS). These technologies have contributed to the molecular characterization of the myelodysplastic syndromes (MDS) and chronic myelomonocytic leukaemia (CMML), through the identification of recurrent gene mutations, which are present in >80% of patients. These mutations contribute to a better classification and risk stratification of the patients. Currently, clinical laboratories include NGS genomic analyses in their routine clinical practice, in an effort to personalize the diagnosis, prognosis and treatment of MDS and CMML. NGS technologies have reduced the cost of large-scale sequencing, but there are additional challenges involving the clinical validation of these technologies, as continuous advances are constantly being made. In this context, it is of major importance to standardize the generation, analysis, clinical interpretation and reporting of NGS data. To that end, the Spanish MDS Group (GESMD) has expanded the present set of guidelines, aiming to establish common quality standards for the adequate implementation of NGS and clinical interpretation of the results, hoping that this effort will ultimately contribute to the benefit of patients with myeloid malignancies.
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    Comparative genomic hybridization and amplotyping by arbitrarily primed PCR in stage A B-CLL
    (Elsevier, 2001) Cigudosa, J.C. (Juan Cruz); Perucho, M. (Manuel); Matutes, E. (Estella); Chaganti, R. (R.); Zudaire, I. (Isabel); Ardanaz, M.T. (M.T.); Calasanz-Abinzano, M.J. (Maria Jose); Odero, M.D. (Maria Dolores); Rao, P.H. (Pulivarthi H.); Martin-Subero, J.I. (Jose Ignacio); Soto, J.L. (José L.)
    Cytogenetic analysis is useful in the diagnosis and to assess prognosis of B-cell chronic lymphocytic leukemia (B-CLL). However, successful cytogenetics by standard techniques has been hindered by the low in vitro mitotic activity of the malignant B-cell population. Fluorescence in situ hybridization (FISH) has become a useful tool, but it does not provide an overall view of the aberrations. To overcome this hurdle, two DNA-based techniques have been tested in the present study: comparative genomic hybridization (CGH) and amplotyping by arbitrarily primed PCR (AP-PCR). Comparative genomic hybridization resolution depends upon the 400-bands of the human standard karyotype. AP-PCR allows detection of allelic losses and gains in tumor cells by PCR fingerprinting, thus its resolution is at the molecular level. Both techniques were performed in 23 patients with stage A B-CLL at diagnosis. The results were compared with FISH. The sensitivity of AP-PCR was greater than CGH (62% vs. 43%). The use of CGH combined with AP-PCR allowed to detect genetic abnormalities in 79% (15/19) of patients in whom G-banding was not informative, providing a global view of the aberrations in a sole experiment. This study shows that combining these two methods with FISH, makes possible a more precise genetic characterization of patients with B-CLL.
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    NUP98 is fused to adducin 3 in a patient with T-cell acute lymphoblastic leukemia and myeloid markers, with a new translocation t(10;11)(q25;p15)
    (American Association for Cancer Research, 2003) Cigudosa, J.C. (Juan Cruz); Sala, F. (Francisco); Gorosquieta, A. (A.); Perez-Equiza, K. (Katy); Lahortiga, I. (Idoya); Vizmanos-Pérez, J.L. (José Luis); Vazquez, I. (Iria); Larrayoz, M.J. (María J.); Calasanz-Abinzano, M.J. (Maria Jose); Odero, M.D. (Maria Dolores); Aguirre-Ena, X. (Xabier)
    The nucleoporin 98 gene (NUP98) has been reported to be fused to 13 partner genes in hematological malignancies with 11p15 translocations. Twelve of them have been identified in patients with myeloid neoplasias and only 1, RAP1GDS1 (4q21), is fused with NUP98 in five patients with T-cell acute lymphoblastic leukemia (T-ALL). Three of these patients coexpressed T and myeloid markers, suggesting the specific association of t(4;11)(q21;p15) with a subset of T-ALL originating from an early progenitor, which has the potential to express mature T-cell antigens as well as myeloid markers. We describe here a new NUP98 partner involved in a t(10;11)(q25;p15) in a patient with acute biphenotypic leukemia, showing coexpression of mature T and myeloid markers. The gene involved, located in 10q25, was identified as ADD3 using 3'-RACE. ADD3 codes for the ubiquitous expressed subunit gamma of the adducin protein, and it seems to play an important role in the skeletal organization of the cell membrane. Both NUP98-ADD3 and ADD3-NUP98 fusion transcripts are expressed in the patient. This is the second partner of NUP98 described in T-ALL. Adducin shares with the product of RAP1GDS1, and with all of the nonhomeobox NUP98 partners, the presence of a region with significant probability of adopting a coiled-coil conformation. This region is always retained in the fusion transcript with the NH(2) terminus FG repeats of NUP98, suggesting an important role in the mechanism of leukemogenesis.