grupo

Group name: Genetics of hematological malignancies and associated complications

    Group leader
  • Manuel Jurado Chacón
  • Juan Sainz Pérez
  • PHD Students
  • Rafael Ríos Tamayo

Presentation Video

SCIENTIFIC INTEREST AREAS

In the past decades, it has become clear that hematological malignancies such as acute leukemias (ALL and AML), monoclonal gammopathies (MGUS and MM), lymphoproliferative disorders (LPD) and myelodysplastic syndromes (MDS) can be caused by a variety of mechanisms, including the inactivation of tumor suppressor genes, activation of oncogenes, and genomic instability. These oncogenic processes arise from the accumulation of many genetic and epigenetic lesions.

Although conventional cytogenetic techniques (karyotyping and fluorescence in situ hybridization) have lead to the identification of large number of chromosomal aberrations and mutations involved in the development and/or progression of hematological malignancies, it is well known that these techniques have some important limitations. The spectacular technological advances in the area of both functional and structural genomics and the exponentially increasing amount of data being generated have shown that many types of genetic variations may affect the risk of developing hematological malignancies. New genomics approaches have contributed to the emergence of an important new dimension into biomedical research with a notorious progress in understanding the structure and function of the human genome as well as its role on cancer biology. Individual genetic variants, either alone or in combination with others, can contribute to change individual cancer risk. However, up to date, only a few genetic biomarkers have been reliably associated with hematological malignancies and disease progression.

For this reason, our research group is focused on the identification of genetic variants (SNPs, indel, CNVs, etc...) associated with hematological malignancies, cancer progression and cancer-related complications such as graft versus host disease and opportunistic infections. In parallel, our group is also aimed at analyzing the interaction of particular genetic variants and cancer risk (gender, obesity, type 2 diabetes, etc…), life-style and environmental factors as well as the characterization of genetic factors contributing to drug resistance. Hypothesis-driven candidate gene and genome-wide association (GWAS) studies along with CGH-A (comparative genomic arrays hybridation) and next-generation sequencing provide an unprecedented opportunity for a comprehensive analysis of the genetic factors involved in hematological malignancies and related traits.

The use of these recently developed methods coupled with genome-wide expression analysis can now help us to identify susceptibility genes for hematlogical malignancies leading to better diagnositics and genotype-guided therapeutic strategies. Likewise, these new technologies have begun to unravel the complex genetic architecture that underlies the diversity of cancers allowing the potential identification of new therapeutic targets.

RESEARCH AREAS

  • RESEARCH LINE 1: GENETICS OF MONOCLONAL GAMMOPATHIES: MGUS AND MM
    Multiple myeloma (MM) is a very heterogeneous hematologic malignancy that arises from a premalignant stage, the monoclonal gammopathy of undetermined significance (MGUS) or an intermediate stage called smoldering myeloma (SMM). Despite recent progress in the understanding of its pathogenesis, further research is warranted, as the transformation from either MGUS or SMM to MM is still not preventable and the disease is not curable. MM occurs as consequence of the accumulation of numerous genetic alterations such as translocations involving immunoglobulin heavy chain (IgH) locus (11q13, 4p16, 16q23, 21q12, and 6p21), deletions at long arm of chromosome 13, and multiple trisomies (chromosomes 3, 5, 9, 11, 15, 19 and 21) leading to a deregulation of many genes involved in cell proliferation, differentiation and migration (i.e., D-type cyclins, FGFR3 and MMSET among others). Several of these alterations can appear years before to the onset of MM, suggesting that additional genetic or epigenetic alterations must contribute to the development of the disease. In this regard, recent studies carried out by our group (and others) have shown that the presence of single nucleotide polymorphisms (SNPs) can potentially influence the development of the disease as well as its progression. Thus, the main purpose of our research group is to determine the genetic polymorphisms associated with MM and its progression as well as to identify those SNPs that can also influence on drug disposition and response. This research is conducted within the context of the IMMEnSE (International Multiple Myeloma rESEarch) consortium.
    • RESEARCH LINE 2: GENETICS OF HEMATOLOGICAL MALIGNANCIES

      Most of the hematological malignancies are genetically characterized by recurrent aneuploidies and chromosomal translocations but these alterations do not account for the genetic basis of these diseases, suggesting that additional genetic alterations may also confer susceptibility or resistance to a disease. Thereby, we aim to explore the possibility that SNPs could be involved in susceptibility to malignant hemopathies and/or adverse drug reactions.
    • RESEARCH LINE 3: CANCER-RELATED INFECTIONS: INVASIVE PULMONARY ASPERGILLOSIS

      Invasive pulmonary aspergillosis (IPA) is an opportunistic and fulminant infection caused by inhalation of Aspergillus spp. spores. The invasive stage of the disease is characterized by hyphal invasion and destruction of pulmonary tissue, which are most frequently observed in patients with pre-existing infections or lung damage. Despite the use of new antifungal drugs and the development of more sophisticated methods of diagnosis, the incidence of IPA continues to rise. Epidemiologic studies have demonstrated that hematological patients with similar clinical conditions and extrinsic risk factors vary in their susceptibility to IPA, suggesting a possible genetic predisposition to develop the disease. Genetic factors explain, at least in part, why some people resist infection more successfully than others, and gene disruptions can cause fatal vulnerability to specific pathogens. Indeed, single-nucleotide polymorphisms (SNPs) in the promoter and coding regions of cytokine genes have been associated with changes in cytokine production or function and may therefore influence susceptibility to infections. Identification of patients who are more susceptible to infection could facilitate the implementation of effective prevention strategies.

      In the context of an international consortium, AspBIOmics, our group is focused on the identification of genetic variants associated with IPA infection in order to design and implement risk-adapted therapeutic strategies. On the other hand, although it is now well recognized that SNPs in genes modulating immune response are likely to be determinants of host susceptibility to fungal infections, so far little is known regarding the biological significance of these variants. For this reason, we also aim to determine the biological consequences of genetic variations associated with IPA infection. Besides individual genetic susceptibility of the host, with this consortium we also propose to develop and evaluate a battery of in vitro assays for a comprehensive multimodality analysis including the detection of Aspergillus elements (RNA, polysaccharides, proteins) and host factors including cytokine profiles. Existing diagnostic parameters will be included in the analysis to validate the improvement of the methods under development over the existing ones. For a more detailed information regarding AspBIOmics consortium, visit our website (http://www.aspBIOmics.eu).
    • RESEARCH LINE 4:MESENCHIMAL STEM CELLS INFUSION AS POTENTIAL TREATMENT FOR GRAFT-VERSUS-HOST-DISEASE

      Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a potentially curative therapy for patients diagnosed with hematolgical malignancies. This therapeutic approach has been associated with high toxicity levels caused by the development of either acute or chronic graft-versus-host-disease (GVHD), which considerably increase morbidity and mortality rates. Within recent years, the incidence of GVHD has increased significantly among allo-transplanted patients and, although its pathogenesis, clinical presentation, long-term complications (malignancies, growth disorders and nutrition) and histology have been extensively studied, so far no optimal therapy has been defined.

      Due to their immunomodulatory properties, MSCs are considered to be an attractive tool for the treatment of autoimmune diseases. MSCs reduce lymphocyte proliferation by interventions that specifically inhibit cell division and, at least in vitro, alloantigen-mediated cytotoxic T lymphocytes activation. Recently it has also been suggested that infused mesenchymal stem cells (MSCs) might be an optional strategy for the treatmetn of GVHD as they are a component of the marrow microenvironment that, along with other cellular elements such as macrophages, fibroblasts, adipocytes, and osteoprogenitor and endothelial cells, contribute to the support of hematopoiesis and bone homeostasis. Nonetheless, there are still many issues to be clarified to optimize their therapeutic use (number of infusions, dose of administred cells, possible synergism with other therapies, their role in the process of relapse or in the occurrence of lethal infections). Based on these facts, our main objective is to analyze the safety and feasibility of human MSCs infusion for the treatment of chronic GVHD and to optimize and standardize processes to obtain and produce these cells as well as to evaluate the effect of MSCs infusion on T cell populations and cytokine production in patients treated with this novel therapy.
    • OTHER AREAS OF INTEREST

      • GENETIC BASIS OF AUTOIMMUNE DISEASES: RHEUMATOID ARTHRITIS.

      Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic inflammatory activity in the synovial joints often leading to progressive cartilage and bone destruction. RA is three times more frequent in women than men and emerging data suggest that women are more likely to present a worse course of the disease and to become severely disabled. Although different hypotheses concerning sex-related differences in RA incidence and severity have been generated, the hypothesis suggesting a sexual dimorphism in the intensity of immune responses remains as one of the most probable mechanisms in promoting and establishing a different synovial membrane inflammation and, subsequently, different levels of cartilage and bone erosion. Women have higher immunoglobulin levels than men, they show stronger Th1-type cell-mediated immune responses and they have higher absolute numbers of CD4+ lymphocytes and a more proactive cytokine profile, which likely contribute to their increased autoimmune responses. Experimental studies in rodents have also shown different immune responses between female and male animals and an equivalent sexual dimorphism in the incidence of RA. The underlying reasons for this gender bias are still unknown, but studies in monozygotic twins have suggested that genetic factors may, at least in part, account for sex-related differences in the immune responses and, consequently, in the susceptibility to autoimmune diseases. Genetic factors implicated in RA have been widely studied using both candidate genes and whole-genome screens but, so far, only a few studies have investigated the link between SNPs and the gender-associated differences in susceptibility to RA. Considering these facts, our research group is focused on the identification of genetic variants (tagging and potentially functional SNPs) within immune-related genes associated with the risk to develop RA. In addition, our group is studying whether gender and environmental factors interact to determine the risk of the disease.

      • GENETICS OF SOLID TUMORS

      In the context of both national and international research collaborations, our group is trying to assess whether genetic factors either alone or by interaction with environmental factors may play a role in determining the most common kind of cancers (colorectal, stomach, breast and prostate cancer). To this end, our group is recruiting cases of different cancers and healthy controls to carry out both candidate gene and genome-wide association (GWA) studies, very useful approaches for identifying genes associated with cancer.

    TECHNOLOGY PLATFORMS

    High-througput genotyping technologies

    • Genotipado Masivo - Infinium® HD Beadchips, Illumina® Technology
    • iSelect HD Custom Genotyping, Illumina® Technology
    • Genotipado a pequeña escala - Tecnología 7500 Real Time PCR System (TaqMan® Applied Biosystems, KASPar® KBiosciences)
    • ImmunoChip (Illumina® Technology)

    Masive sequencing (Next generation sequencing)

    • Sequencing
    • IIlumina® Sequencing Technology

    Gene expression

    • CodeLink Plataform ( Applied Microarrays)
    • CodeLink Human Whole Genome Arrays
    • CodeLink Mouse Whole Genome Arrays

    Primary cell cultures Functional assays

    • Reporter assays (luciferase assays)
    • Expression vector assays
    • EMSA

    FUNDING

    • ERA-NETPathogenomics
    • Instituto de Salud Carlos III
    • Consejería de Innovación, Ciencia y Empresa. Junta de Andalucía (Proyectos de Excelencia, Proyectos del Servicio Andaluz de Salud)
    • CELGENE
    • ROCHE-PHARMA
    • Fundación Andaluza de Reumatología

    SELECTED PUBLICATIONS

    Cáliz R, Canet LM, Lupiañez CB, Canhao H, Escudero A, Filipescu I, Segura-Catena J, Soto-Pino MJ, Expósito-Ruiz M, Ferrer MA, García A, Romani L, González-Utrilla A, Vallejo T, Pérez-Pampín E, Hemminki K, Försti A, Collantes E, Fonseca JE, Sainz J. Gender-specific effects of genetic variants within Th1 and Th17 cell-mediated immune response genes on the risk of developing rheumatoid arthritis. Plos One 2013; 8 (8): E72732.

    Lu S, Bevier M, Huhn S, Sainz J, Lascorz J, Pardini B, Naccarati A, Huhn S, Vodickova L, Novotny J, Hemminki, K, Vodicka P, Försti A. Single nucleotide polymorphisms within three C-type lectin genes associate with colorectal, cancer susceptibility and clinical outcome. International Journal of Cancer 2013; 133 (10): 2325-2333.

    Martino A, Sainz J, Reis RM, Moreno V, Buda G, Lesueur F, Marques H, García-Sanz R, Ríos R, Stein A, Dumontet C, Gemignani F, Rossi AM, Landi S, Jurado M, Petrini M, Jamroziak K, Campa D, Canzian F. Polymorphisms in regulators of xenobiotic transport and metabolism genes PXR and CAR do not affect multiple myeloma risk: a case-control study in the context of IMMEnSE consortium. Journal of Human Genetics 2013; 58 (3): 155-159.

    Sainz J, Rudolph A, Hoffmeister M, Frank B, Brenner H, Chang-Claude J, Hemminki K, Försti A. Effect of type-2 diabetes predisposing genetic variants on colorectal cancer risk. The Journal of Clinical Endocrinology and Metabolism 2012; 97 (5): E845-851.

    Martino A, Campa D, Jamroziak K, Reis RM, Sainz J, Buda G, García-Sanz R, Lesueur F, Marques H, Moreno V, Jurado M, Ríos R, Szemraj-Rogucka Z, Szemraj J, Tjønneland A, Overvad K, Vangsted AJ, Vogel U, Mikala G, Kádár K, Szombath G, Varkonyi J, Orciuolo E, Dumontet C, Gemignani F, Rossi AM, Landi S, Petrini M, Houlston RS, Hemminki K, Canzian F. Impact of polymorphic variation at 7p15.3, 3p22.1 and 2p23.3 loci on risk of multiple myeloma. British Journal of Haematology 2012; 158 (6): 805-809.

    Campa D, Martino A, Sainz J, Buda G, Jamroziak K, Weinhold N, Vieira Reis RM, García-Sanz R,Jurado M, Ríos R, Szemraj-Rogucka Z, Marques H, Lesueur F, Bugert P, Moreno V, Szemraj J,Orciuolo E, Gemignani F, Rossi AM, Dumontet C, Petrini M, Goldschmidt H, Landi S, Canzian F. Comprehensive investigation of genetic variation in the 8q24 region and multiple myeloma risk in the IMMEnSE consortium. British Journal of Haematology 2012; 157 (3): 331-338.

    Campa D, Sainz J, Rudolph A, Pardini B, Naccarati A, Vodickova L, Chang-Claude J, Brenner H, Novotny J, Försti A, Buch S, von Schönfels W, Hampe J, Schafmayer C, Völzke H, Hemminki K, Pavel Vodicka, Roberto Barale and Federico Canzian. A gene-wide investigation on polymorphisms in the MDR1/ABCB1 trasporter and susceptibility to colorectal cancer. Plos One 2012; 7 (3): e32784.

    Sainz J, Lupiañez CB, Segura-Catena J, Vazquez L, Ríos R, Oyonarte S, Hemminki K, Försti A, Jurado M. Dectin-1 and DC-SIGN polymorphisms associated with Invasive Pulmonary Aspergillosis infection. Plos One 2012; 7 (2): e32273.

    Martino A, Campa D, Buda G, Sainz J, García-Sanz R, Jamroziak K, Vieira-Reis RM, Weinhold N, Jurado M, Ríos R, Szemraj-Rogucka Z, Marques H, Stein A, Kumar R, Orciuolo E, Gemignani F, Landi S, Goldsmidt H, Petrini M, Dumontet C, Canzian F, Rossi AM. Polymorphisms in xenobiotic transporters ABCB1, ABCG2, ABCC2, ABCC1, ABCC3 and Multiple Myeloma risk: a case-control study in the context of the IMMEnSE (International Multiple Myeloma rESEarch) consortium. Leukemia 2012; 26 (6): 1419-1422.

    Sainz J, García F, Blanco A, Concha A. Gene expression profiling of early differentiation in mouse embryonic stem cells. International Journal of Developmental Biology 2011; 55: 995-1006

    ADDITIONAL INFORMATION

    CONSORTIUMS AND MULTICENTRIC STUDIES:

    • AspBIOMics (Invasive aspergillosis: Biomarkers for prevention, diagnosis and treatment response) Information about scientific members and centres agreeing to participate at available at www.aspbiomics.eu
      PROF. DR. HERMANN EINSELE, Medizinische Klinik und Poliklinik II, University of Würzburg, Germany DR. Juergen Löffler, Julius-Maximilians-Universität Würzburg, Medizinische Klinik & Poliklinik II, Würzburg, Germany. PROF. DR. AXEL A. BRAKHAGE, Molecular and Applied Microbiology, Leibniz Institute for Natural Product Research and Infection Biology, Hans-Knöll-Institue (HKI) and Microbiology and Molecular Biology, Friedrich-Schiller-University, Jena PROFESSOR JEAN PAUL LATGÉ, Institute Pasteur, Paris, France DR. ALAIN TROESCH, Global Executive Director – R&D Molecular Biology bioMérieux, Centre Christophe Mérieux, Grenoble, France DR. CORNELIA LASS-FLÖRL, Division of Hygiene and Medical Microbiology, Innsbruck Medical University, Innsbruck. BIOMÉRIEUX, Institut Mérieux group, France
    • IMMEnSE (International Multiple Myeloma rESEarch) Consortium members:
      DR. CANZIAN, DR. CAMPA AND DR. MARTINO Genomic Epidemiology Group, German Cancer Research Center, Heidelberg, Germany. DR. GABRIELE BUDA, Department of Oncology, Transplants and Advanced Technologies, Section of Hematology, Pisa University, Via Roma 67, 56100, Pisa, Italy DR. FELIPE DE ARRIBA DE LA FUENTE, Servicio de Hematología, Hospital Morales Meseguer, Murcia, Spain DR. RAMÓN GARCÍA-SANZ, Servicio de Hematología, Hospital de Salamanca, Univesidad de Salamanca-Consejo Superior de Investigaciones Científicas, Salamanca, Spain. DR. KRZYSZTOF JAMROZIACK, Department of Hematology, Medical University of Lodz, Lodz, Poland. DR. RUI MANUEL VIEIRA REIS, Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Braga, Portugal DR. HERLANDER MARQUES, Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Braga, Portugal DR. NIELS WEINHOLD, Medizinische Klinik V, Universitaetsklinikum Heidelberg, Heidelberg, Germany DR. RAJIV KUMAR, Molecular Genetic Epidemiology Group, German Cancer Research Center, Heidelberg, Germany. DR. ENRICO ORCIUOLO, Department of Oncology, Transplants and Advanced Technologies, Section of Hematology, Pisa University, Pisa, Italy DR. FEDERICA GEMIGNANI, Department of Biology, Section of Genetics, University of Pisa, Pisa, Italy DR. STEFANO LANDI, Department of Biology, Section of Genetics, University of Pisa, Pisa, Italy DR. HARTMUT GOLDSCHMIDT, Medizinische Klinik V, Universitaetsklinikum Heidelberg, Heidelberg, Germany DR. MARIO PETRINI, Department of Oncology, Transplants and Advanced Technologies, Section of Hematology, Pisa University, Pisa, Italy DR. CHARLES DUMONTET,INSERM U590, Laboratoire de Cytologie Analytique, Faculte de Medecine Rockefeller, Universite Claude Bernard Lyon I, Lyon, France. DR. ANNA MARÍA ROSSI, Department of Biology, Section of Genetics, University of Pisa, Pisa, Italy DR. JOAQUIN MARTÍNEZ, Hematology department, 12 de Octubre Hospital, Madrid, Spain DR. JOSÉ HERNÁNDEZ MARTÍN, Servicio de Hematología, Hospital General de Segovia, Segovia, Spain

    ADDITIONAL COLLABORATIONS:

    • RHEUMATOID ARTHRITIS GROUP (VIRGEN DE LAS NIEVES UNIVERSITY HOSPITAL) DR. RAFAEL CÁLIZ CÁLIZ, Section of Rheumatology, Virgen de las Nieves University Hospital, Granada, Spain.
    • MCC-SPAIN: (http://mccspain.org/). DR. JOSÉ JUAN JIMÉNEZ MOLEÓN, Department of Preventive Medicine and Public Health, University of Granada, Spain.
    • GERMAN CANCER RESEARCH CENTER PROF. KARI HEMMINKI AND DR. ASTA FÖRSTI, Molecular Genetic Epidemiology Group, German Cancer Research Center, Heidelberg, Germany.
    • SPANISH GROUP OF STEM CELL TRANSPLANTATION (GETH) DR. LOURDES VAZQUEZ (Coordinator of the Spanish Group of Infections; University Hospital of Salamanca)
    • BLOOD TRANSFUSION REGIONAL CENTRE AND SECTORIAL TISSUE BANK, GRANADA, SPAIN DR. SALVADOR OYONARTE, Facultativo Especialista de Área, Centro Regional de Transfusiones Sanguíneas y Banco Sectorial de Tejidos Granada-Almería. Spain.