José I Martín-Subero

IDIBAPS August Pi i Sunyer Biomedical Research Institute, Barcino, Catalonia, Spain

Are you José I Martín-Subero?

Claim your profile

Publications (118)755.44 Total impact

  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: We investigated DNA methylomes of pediatric B-cell acute lymphoblastic leukemias (B-ALLs) using whole-genome bisulfite sequencing and high-definition microarrays, along with RNA expression profiles. Epigenetic alteration of B-ALLs occurred in two tracks: de novo methylation of small functional compartments and demethylation of large inter-compartmental backbones. The deviations were exaggerated in lamina-associated domains, with differences corresponding to methylation clusters and/or cytogenetic groups. Our data also suggested a pivotal role of polycomb and CTBP2 in de novo methylation, which may be traced back to bivalency status of embryonic stem cells. Driven by these potent epigenetic modulations, suppression of polycomb target genes was observed along with disruption of developmental fate and cell cycle and mismatch repair pathways and altered activities of key upstream regulators. © The Author(s) 2015. Published by Oxford University Press on behalf of Nucleic Acids Research.
    Nucleic Acids Research 02/2015; 43(5). DOI:10.1093/nar/gkv103 · 8.81 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: While analyzing the DNA methylome of multiple myeloma (MM), a plasma cell neoplasm, by whole-genome bisulfite sequencing and high-density arrays, we observed a highly heterogeneous pattern globally characterized by regional DNA hypermethylation embedded in extensive hypomethylation. In contrast to the widely reported DNA hypermethylation of promoter-associated CpG islands (CGIs) in cancer, hypermethylated sites in MM, as opposed to normal plasma cells, were located outside CpG islands and were unexpectedly associated with intronic enhancer regions defined in normal B cells and plasma cells. Both RNA-seq and in vitro reporter assays indicated that enhancer hypermethylation is globally associated with downregulation of its host genes. ChIP-seq and DNase-seq further revealed that DNA hypermethylation in these regions is related to enhancer decommissioning. Hypermethylated enhancer regions overlapped with binding sites of B cell-specific transcription factors (TFs) and the degree of enhancer methylation inversely correlated with expression levels of these TFs in MM. Furthermore, hypermethylated regions in MM were methylated in stem cells and gradually became demethylated during normal B-cell differentiation, suggesting that MM cells either reacquire epigenetic features of undifferentiated cells or maintain an epigenetic signature of a putative myeloma stem cell progenitor. Overall, we have identified DNA hypermethylation of developmentally-regulated enhancers as a new type of epigenetic modification associated with the pathogenesis of MM. Published by Cold Spring Harbor Laboratory Press.
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Prospective identification of patients with chronic lymphocytic leukemia (CLL) destined to progress would greatly facilitate their clinical management. Recently, whole-genome DNA methylation analyses identified three clinico-biological CLL subgroups with an epigenetic signature related to different normal B-cell counterparts. Here, we developed a clinically-applicable method to identify these subgroups and to study their clinical relevance. Using a support vector machine approach, we built a prediction model using five epigenetic biomarkers that was able to accurately classify CLL patients into the three subgroups, namely naive B cell-like, intermediate and memory B cell-like CLL. DNA methylation was quantified by highly reproducible bisulfite pyrosequencing (BPS) assays in two independent CLL series. In the initial series (n=211), the three subgroups showed differential levels of IGHV mutation (P<0.001) and VH usage (P<0.03), as well as different clinical features and outcome in terms of time-to-first-treatment (TTT) and overall survival (P<0.001). A multivariate Cox model showed that epigenetic classification was the strongest predictor of TTT (P<0.001) along with Binet stage (P<0.001). These findings were corroborated in a validation series (n=97). In this study, we developed a simple and robust method using epigenetic biomarkers to categorize CLLs into three subgroups with different clinico-biological features and outcome.Leukemia accepted article preview online, 25 August 2014 doi:10.1038/leu.2014.252.
    Leukemia 08/2014; DOI:10.1038/leu.2014.252 · 9.38 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: In a subset of imprinting disorders caused by epimutations, multiple imprinted loci are affected. Familial occurrence of multilocus imprinting disorders is rare. We have investigated the clinical and molecular features of a familial DNA-methylation disorder. Tissues of affected individuals and blood samples of family members were investigated by conventional and molecular karyotyping. Sanger sequencing and RT-PCR of imprinting-associated genes (NLRP2, NLRP7, ZFP57, KHDC3L, DNMT1o), exome sequencing and locus-specific, array-based and genome-wide technologies to determine DNA-methylation were performed. In three offspring of a healthy couple, we observed prenatal onset of severe growth retardation and dysmorphism associated with altered DNA-methylation at paternally and maternally imprinted loci. Array-based analyses in various tissues of the offspring identified the DNA-methylation of 2.1% of the genes in the genome to be recurrently altered. Despite significant enrichment of imprinted genes (OR 9.49), altered DNA-methylation predominately (90.2%) affected genes not known to be imprinted. Sequencing of genes known to cause comparable conditions and exome sequencing in affected individuals and their ancestors did not unambiguously point to a causative gene. The family presented herein suggests the existence of a familial disorder of DNA-methylation affecting imprinted but also not imprinted gene loci potentially caused by a maternal effect mutation in a hitherto not identified gene.
    Journal of Medical Genetics 04/2014; 51(6). DOI:10.1136/jmedgenet-2013-102149 · 5.64 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The precise regulation of S-phase-specific genes is critical for cell proliferation. How the repressive chromatin configuration mediated by the retinoblastoma protein and repressor E2F factors changes at the G1/S transition to allow transcription activation is unclear. Here we show ChIP-on-chip studies that reveal that the chromatin remodeller CHD8 binds ∼2000 transcriptionally active promoters. The spectrum of CHD8 target genes was enriched in E2F-dependent genes. We found that CHD8 binds E2F-dependent promoters at the G1/S transition but not in quiescent cells. Consistently, CHD8 was required for G1/S-specific expression of these genes and for cell cycle re-entry on serum stimulation of quiescent cells. We also show that CHD8 interacts with E2F1 and, importantly, loading of E2F1 and E2F3, but not E2F4, onto S-specific promoters, requires CHD8. However, CHD8 recruiting is independent of these factors. Recruiting of MLL histone methyltransferase complexes to S-specific promoters was also severely impaired in the absence of CHD8. Furthermore, depletion of CHD8 abolished E2F1 overexpression-dependent S-phase stimulation of serum-starved cells, highlighting the essential role of CHD8 in E2F-dependent transcription activation.
    Nucleic Acids Research 11/2013; 42(4). DOI:10.1093/nar/gkt1161 · 8.81 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Chronic lymphocytic leukemia (CLL) has heterogeneous clinical and biological behavior. Whole-genome and -exome sequencing has contributed to the characterization of the mutational spectrum of the disease, but the underlying transcriptional profile is still poorly understood. We have performed deep RNA sequencing in different subpopulations of normal B-lymphocytes and CLL cells from a cohort of 98 patients, and characterized the CLL transcriptional landscape with unprecedented resolution. We detected thousands of transcriptional elements differentially expressed between the CLL and normal B cells, including protein coding genes, non-coding RNAs and pseudogenes. Transposable elements are globally de-repressed in CLL cells. In addition, two thousand genes - most of which are not differentially expressed - exhibit CLL-specific splicing patterns. Genes involved in metabolic pathways showed higher expression in CLL, while genes related to spliceosome, proteasome and ribosome were among the most downregulated in CLL. Clustering of the CLL samples according to RNA-seq derived gene expression levels unveiled two robust molecular subgroups, C1 and C2. C1/C2 subgroups and the mutational status of the immunoglobulin heavy variable (IGHV) region were the only independent variables in predicting time to treatment in a multivariate analysis with main clinico-biological features. This subdivision was validated in an independent cohort of patients monitored through DNA microarrays. Further analysis shows that B-cell receptor (BCR) activation in the microenvironment of the lymph node may be at the origin of the C1/C2 differences.
    Genome Research 11/2013; DOI:10.1101/gr.152132.112 · 13.85 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Mantle cell lymphoma (MCL) is an aggressive tumor, but a subset of patients may follow an indolent clinical course. To understand the mechanisms underlying this biological heterogeneity, we performed whole-genome and/or whole-exome sequencing on 29 MCL cases and their respective matched normal DNA, as well as 6 MCL cell lines. Recurrently mutated genes were investigated by targeted sequencing in an independent cohort of 172 MCL patients. We identified 25 significantly mutated genes, including known drivers such as ataxia-telangectasia mutated (ATM), cyclin D1 (CCND1), and the tumor suppressor TP53; mutated genes encoding the anti-apoptotic protein BIRC3 and Toll-like receptor 2 (TLR2); and the chromatin modifiers WHSC1, MLL2, and MEF2B. We also found NOTCH2 mutations as an alternative phenomenon to NOTCH1 mutations in aggressive tumors with a dismal prognosis. Analysis of two simultaneous or subsequent MCL samples by whole-genome/whole-exome (n = 8) or targeted (n = 19) sequencing revealed subclonal heterogeneity at diagnosis in samples from different topographic sites and modulation of the initial mutational profile at the progression of the disease. Some mutations were predominantly clonal or subclonal, indicating an early or late event in tumor evolution, respectively. Our study identifies molecular mechanisms contributing to MCL pathogenesis and offers potential targets for therapeutic intervention.
    Proceedings of the National Academy of Sciences 10/2013; 110(45). DOI:10.1073/pnas.1314608110 · 9.81 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The diagnosis of mantle cell lymphoma (MCL) can be difficult, especially when no t(11;14) translocation and cyclin D1 overexpression can be detected. In such cases, the transcription factor SOX11 represents an important diagnostic marker, as it is expressed in most MCLs and, in particular, in all cyclin D1-negative MCLs reported so far. A reliable anti-SOX11 antibody is therefore a very useful tool for routine diagnosis. Here, we characterize the new monoclonal anti-SOX11 antibodies, suitable for Western blot assay and immunohistochemistry (IHC) on formalin-fixed paraffin-embedded tissue; we tested them on a large series of primary lymphoid tumors and compared these results with those of other routinely used antibodies. Moreover, we show that IHC results depend on transcription levels of SOX11, which suggests that posttranscriptional and posttranslational modifications do not significantly affect cutoff levels for IHC detection of SOX11.
    The American journal of surgical pathology 10/2013; DOI:10.1097/PAS.0b013e3182a43996 · 4.59 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The central nervous system has a pattern of gene expression that is closely regulated with respect to functional and anatomical regions. DNA methylation is a major regulator of transcriptional activity, and aberrations in the distribution of this epigenetic mark may be involved in many neurological disorders, such as Alzheimer's disease. Herein, we have analysed 12 distinct mouse brain regions according to their CpG 5'-end gene methylation patterns and observed their unique epigenetic landscapes. The DNA methylomes obtained from the cerebral cortex were used to identify aberrant DNA methylation changes that occurred in two mouse models of Alzheimer's disease. We were able to translate these findings to patients with Alzheimer's disease, identifying DNA methylation-associated silencing of three targets genes: thromboxane A2 receptor (TBXA2R), sorbin and SH3 domain containing 3 (SORBS3) and spectrin beta 4 (SPTBN4). These hypermethylation targets indicate that the cyclic AMP response element-binding protein (CREB) activation pathway and the axon initial segment could contribute to the disease.
    Brain 09/2013; DOI:10.1093/brain/awt237 · 10.23 Impact Factor
  • Marta Kulis, Ana C Queirós, Renée Beekman, José I Martín-Subero
    [Show abstract] [Hide abstract]
    ABSTRACT: Ever since the discovery of DNA methylation at cytosine residues, the role of this so called fifth base has been extensively studied and debated. Until recently, the majority of DNA methylation studies focused on the analysis of CpG islands associated to promoter regions. However, with the upcoming possibilities to study DNA methylation in a genome-wide context, this epigenetic mark can now be studied in an unbiased manner. As a result, recent studies have shown that not only promoters but also intragenic and intergenic regions are widely modulated during physiological processes and disease. In particular, it is becoming increasingly clear that DNA methylation in the gene body is not just a passive witness of gene transcription but it seems to be actively involved in multiple gene regulation processes. In this review we discuss the potential role of intragenic DNA methylation in alternative promoter usage, regulation of short and long non-coding RNAs, alternative RNA processing, as well as enhancer activity. Furthermore, we summarize how the intragenic DNA methylome is modified both during normal cell differentiation and neoplastic transformation.
    Biochimica et Biophysica Acta 08/2013; DOI:10.1016/j.bbagrm.2013.08.001 · 4.66 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Mantle cell lymphoma (MCL) is a B-cell neoplasm with an aggressive clinical behaviour characterized by the t(11;14)(q13;q32) and cyclin D1 overexpression. To clarify the potential contribution of altered DNA methylation in the development and/or progression of MCL we performed genome-wide methylation profiling of a large cohort of primary MCL tumors (n=132), MCL cell lines (n=6), and normal lymphoid tissue samples (n=31), using the Infinium HumanMethylation27 BeadChip. DNA methylation was compared to gene expression, chromosomal alterations, and clinicopathological parameters. Primary MCL displayed a heterogeneous methylation pattern dominated by DNA hypomethylation when compared to normal lymphoid samples. A total of 454 hypermethylated and 875 hypomethylated genes were identified as differentially methylated in at least 10% of primary MCL. Annotation analysis of hypermethylated genes recognized WNT pathway inhibitors and several tumor suppressor genes as frequently methylated, and a substantial fraction of these genes (22%) showed a significant downregulation of their transcriptional levels. Furthermore, we identified a subset of tumors with extensive CpG methylation that had an increased proliferation signature, higher number of chromosomal alterations, and poor prognosis. Our results suggest that a subset of MCL displays a dysregulation of DNA methylation characterized by the accumulation of CpG hypermethylation highly associated with increased proliferation that may influence the clinical behavior of the tumors. © 2013 Wiley Periodicals, Inc.
    International Journal of Cancer 07/2013; DOI:10.1002/ijc.28321 · 5.01 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Most DNA methylation studies in Classic Philadelphia-negative myeloproliferative neoplasms have been performed on a gene-by-gene basis. Therefore, a more comprehensive methylation profiling is needed to study the implications of this epigenetic mark in myeloproliferative neoplasms. Here, we have analyzed 71 chronic (24 polycythaemia vera, 23 essential thrombocythaemia and 24 primary myelofibrosis) and 13 transformed myeloproliferative neoplasms using genome-wide DNA methylation arrays. The three types of chronic Philadelphia-negative myeloproliferative neoplasms showed a similar aberrant DNA methylation pattern when compared to control samples. Differentially methylated regions were enriched in a gene network centered on the NF-κB pathway, indicating that they may be involved in the pathogenesis of these diseases. In the case of transformed myeloproliferative neoplasms we detected an increased number of differentially methylated regions with respect to chronic myeloproliferative neoplasms. Interestingly, these genes were enriched in a list of differentially methylated regions in primary acute myeloid leukemia and in a gene network centered around the IFN pathway. Our results suggest that alterations in the DNA methylation landscape play an important role in the pathogenesis and leukaemic transformation of myeloproliferative neoplasms. The therapeutically modulation of epigenetically-deregulated pathways may allow us to design targeted therapies for these patients.
    Haematologica 05/2013; DOI:10.3324/haematol.2013.084160 · 5.87 Impact Factor
  • José I Martín-Subero, Carlos López-Otín, Elías Campo
    [Show abstract] [Hide abstract]
    ABSTRACT: PURPOSE OF REVIEW: Next-generation sequencing of whole genomes, exomes and DNA methylomes in chronic lymphocytic leukemia (CLL) has provided the first comprehensive view of somatic mutations and methylation changes in this disease. This review summarizes the recent findings in this field and their impact on our current understanding of this neoplasm. RECENT FINDINGS: Genomic studies have revealed a remarkable molecular heterogeneity of the disease, with only few genes mutated in up to 10-15% of the patients and a relatively large number of genes recurrently mutated at low frequency. The mutated genes tend to cluster in different pathways that include NOTCH1 signaling, RNA splicing, processing and transport machinery, innate inflammatory response, and DNA damage and cell cycle control, among others. NOTCH1 and SF3B1 mutations are emerging as new drivers of aggressive forms of the disease. Genome-wide methylation studies have shown that CLL transformation is associated with a massive hypomethylation phenomenon frequently affecting the enhancer regions. This epigenetic reprogramming maintains an imprint of the putative cell of origin from naïve and memory B-cells. SUMMARY: Genomic and epigenomic studies of CLL are reshaping our understanding of the disease and provide new perspective for a more individualized diagnosis and new potential therapeutic targets.
    Current opinion in hematology 05/2013; DOI:10.1097/MOH.0b013e32836235dc · 4.05 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: PURPOSE: MicroRNAs (miRs) are post-transcriptional gene regulators that may be useful as diagnostic and/or prognostic biomarkers. We aim to study the expression profiles of a high number of miRs and their relationship with clinicopathological and biological relevant features in leukemic mantle cell lymphomas (MCL). EXPERIMENTAL DESIGN: Expression profiling of 664 miRs was investigated using a high-throughput quantitative real-time PCR platform in 30 leukemic MCL. Statistical and bioinformatic analysis were performed to define miRs associated with different clinicopathological parameters. Gene expression profiling was investigated by microarrays in 16 matching cases to study the potential genes and pathways targeted by selected miRs. The prognostic value of miR-34a was investigated in two independent series of 29 leukemic and 50 nodal MCL. RESULTS: Robust consensus clustering defined two main MCL subgroups with significant differences in the immunoglobulin (IGHV) mutational status, SOX11 expression, genomic complexity and nodal clinical presentation. Supervised analyses regarding IGHV and SOX11 categories identified 17 and 22 miRs differentially expressed, respectively. Enriched targets of these miRs corresponded to relevant pathways in MCL pathogenesis such as DNA stress response, CD40 signaling and chromatin modification. Additionally, we found seven miRs showing prognostic significance independently of IGHV status and SOX11 expression. Among them, miR-34a was also associated with poor prognosis in two independent series of leukemic and nodal MCL, and in cooperation with high expression of the MYC oncogene. CONCLUSIONS: We have identified miRs and target pathways related to clinical and biological variants of leukemic MCL, and validated miR-34a as a prognostic marker in MCL.
    Clinical Cancer Research 05/2013; 19(12). DOI:10.1158/1078-0432.CCR-12-3077 · 8.19 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: About 20% of ovarian carcinomas show alterations of 19p13 and/or 19q13 in the form of added extra material whose origin often is from chromosome 11. Based on earlier spectral karyotype analysis of the ovarian cancer cell line SKOV-3, which shows an unbalanced translocation der(19)t(11;19), the aim of this study was to determine the precise breakpoints of that derivative chromosome. After rough delimitation of the breakpoints of microdissected derivative chromosomes by array analysis, we designed a matrix of primers spanning 11q13.2 and 19p13.2 detecting multiple amplicons on genomic and cDNA. Sequencing the amplicons, accurate localization of both breakpoints on both chromosomes was possible and we found that exon 14 of HOOK2 from chromosome 19 and exon 2 of ACTN3 from chromosome 11 were fused in the derivative chromosome. The breakpoint in the HOOK2 gene was in an intrinsic triplet of nucleic acids leading to a shift in the ACTN3 reading frame in the derivative chromosome. This frameshift alteration should give rise to an early stop codon causing a loss of function of ACTN3. Signals in two-dimensional Western blotting exactly match to calculated molecular mass and the isoelectric point of the fusion protein. © 2013 Wiley Periodicals, Inc.
    Genes Chromosomes and Cancer 05/2013; 52(5). DOI:10.1002/gcc.22048 · 3.84 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Mammary carcinomas developing in SV40 transgenic WAP-T mice arise in two distinct histological phenotypes: as differentiated low-grade and undifferentiated high-grade tumors. We integrated different types of information such as histological grading, analysis of aCGH-based gene copy number and gene expression profiling to provide a comprehensive molecular description of mammary tumors in WAP-T mice. Applying a novel procedure for the correlation of gene copy number with gene expression on a global scale, we observed in tumor samples a global coherence between genotype and transcription. This coherence can be interpreted as a matched transcriptional regulation inherited from the cells of tumor origin and determined by the activity of cancer driver genes. Despite common recurrent genomic aberrations, e.g. gain of chr. 15 in most WAP-T tumors, loss of chr. 19 frequently occurs only in low-grade tumors. These tumors show features of "basal-like" epithelial differentiation, particularly expression of keratin 14. The high-grade tumors are clearly separated from the low-grade tumors by strong expression of the Met gene and by coexpression of epithelial (e.g. keratin 18) and mesenchymal (e.g. vimentin) markers. In high-grade tumors, the expression of the nonmutated Met protein is associated with Met-locus amplification and Met activity. The role of Met as a cancer driver gene is supported by the contribution of active Met signaling to motility and growth of mammary tumor-derived cells. Finally, we discuss the independent origin of low- and high-grade tumors from distinct cells of tumor origin, possibly luminal progenitors, distinguished by Met gene expression and Met signaling.
    International Journal of Cancer 03/2013; 132(6). DOI:10.1002/ijc.27783 · 5.01 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Mantle cell lymphoma (MCL) is one of the most aggressive lymphoid neoplasms whose pathogenesis is not fully understood. The neural transcription factor SOX11 is overexpressed in most MCL but is not detected in other mature B-cell lymphomas or normal lymphoid cells. The specific expression of SOX11 in MCL suggests that it may be an important element in the development of this tumor but its potential function is not known. Here, we show that SOX11 promotes tumor growth in a MCL-xenotransplant mouse model. Using ChIP-chip analysis combined with gene expression profiling upon SOX11 knockdown, we identify target genes and transcriptional programs regulated by SOX11 including the block of mature B-cell differentiation, modulation of cell cycle, apoptosis and stem cell development. PAX5 emerges as one of the major SOX11 direct targets. SOX11 silencing downregulates PAX5, induces BLIMP1 expression and promotes the shift from a mature B-cell into the initial plasmacytic differentiation phenotype, in both primary tumor cells and in an in vitro model. Our results suggest that SOX11 contributes to tumor development by altering the terminal B-cell differentiation program of MCL and provide perspectives that may have clinical implications in the diagnosis and design of new therapeutic strategies.
    Blood 01/2013; 121(12). DOI:10.1182/blood-2012-06-438937 · 9.78 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Neuroblastoma (NB) pathogenesis has been reported to be closely associated with numerous genetic alterations. However, underlying DNA methylation patterns have not been extensively studied in this developmental malignancy. Here, we generated microarray-based DNA methylation profiles of primary neuroblastic tumors. Stringent supervised differential methylation analyses allowed us to identify epigenetic changes characteristic for NB tumors as well as for clinical and biological subtypes of NB. We observed that gene-specific loss of DNA methylation is more prevalent than promoter hypermethylation. Remarkably, such hypomethylation affected cancer-related biological functions and genes relevant to NB pathogenesis such as CCND1, SPRR3, BTC, EGF and FGF6. In particular, differential methylation in CCND1 affected mostly an evolutionary conserved functionally relevant 3' untranslated region, suggesting that hypomethylation outside promoter regions may play a role in NB pathogenesis. Hypermethylation targeted genes involved in cell development and proliferation such as RASSF1A, POU2F2 or HOXD3, among others. The results derived from this study provide new candidate epigenetic biomarkers associated with NB as well as insights into the molecular pathogenesis of this tumor, which involves a marked gene-specific hypomethylation.
    PLoS ONE 11/2012; 7(11):e48401. DOI:10.1371/journal.pone.0048401 · 3.53 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: We have extensively characterized the DNA methylomes of 139 patients with chronic lymphocytic leukemia (CLL) with mutated or unmutated IGHV and of several mature B-cell subpopulations through the use of whole-genome bisulfite sequencing and high-density microarrays. The two molecular subtypes of CLL have differing DNA methylomes that seem to represent epigenetic imprints from distinct normal B-cell subpopulations. DNA hypomethylation in the gene body, targeting mostly enhancer sites, was the most frequent difference between naive and memory B cells and between the two molecular subtypes of CLL and normal B cells. Although DNA methylation and gene expression were poorly correlated, we identified gene-body CpG dinucleotides whose methylation was positively or negatively associated with expression. We have also recognized a DNA methylation signature that distinguishes new clinico-biological subtypes of CLL. We propose an epigenomic scenario in which differential methylation in the gene body may have functional and clinical implications in leukemogenesis.
    Nature Genetics 10/2012; DOI:10.1038/ng.2443 · 29.65 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: 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.
    Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 02/2012; 26(7):1517-26. DOI:10.1038/leu.2012.31 · 9.38 Impact Factor

Publication Stats

4k Citations
755.44 Total Impact Points

Institutions

  • 2012–2015
    • IDIBAPS August Pi i Sunyer Biomedical Research Institute
      Barcino, Catalonia, Spain
  • 2008–2014
    • Christian-Albrechts-Universität zu Kiel
      Kiel, Schleswig-Holstein, Germany
    • Universitätsklinikum Schleswig - Holstein
      Kiel, Schleswig-Holstein, Germany
  • 2013
    • University of Oviedo
      • Department of Biochemistry and Molecular Biology
      Oviedo, Asturias, Spain
  • 2011–2013
    • IDIBELL Bellvitge Biomedical Research Institute
      • Programa de Epigenética y Biología del Cáncer - PEBC
      Barcino, Catalonia, Spain
    • University of Barcelona
      • Department of Pathological Anatomy, Pharmacology and Microbiology
      Barcino, Catalonia, Spain
  • 2003–2013
    • University Medical Center Schleswig-Holstein
      • Department of Pediatrics
      Kiel, Schleswig-Holstein, Germany
    • University College London
      • Department of Pathology
      London, ENG, United Kingdom
  • 2006–2010
    • Centro Nacional de Investigaciones Oncológicas
      Madrid, Madrid, Spain
    • University of Duisburg-Essen
      • Faculty of Medicine
      Essen, North Rhine-Westphalia, Germany
    • Charité Universitätsmedizin Berlin
      • Institute of Pathology
      Berlin, Land Berlin, Germany
    • Universität Ulm
      Ulm, Baden-Württemberg, Germany
  • 2009
    • Institute of Human Genetics
      Amadavad, Gujarāt, India
  • 2006–2007
    • University of Cambridge
      • Department of Pathology
      Cambridge, ENG, United Kingdom
  • 2001–2007
    • Universidad de Navarra
      • Department of Genetics
      Pamplona, Navarre, Spain
  • 2002
    • University of Cologne
      • Department of Neurology
      Köln, North Rhine-Westphalia, Germany