Spotlight

State of the art laboratories

Research in to the basic, epidemiological, preventive, clinical and translational aspects of leukemia and other hematologic malignancies

A New Partnership of Public, Private and Competitive Funding

Patients, Scientists, Doctors; working together to cure leukemia

Research centred on patients

Caring research

News

Latest publications

Velasco I, Salazar P, Giorgetti A, Ramos-Mejía V, Castaño J, Romero-Moya D, Menendez P

Generation of Neurons from Somatic Cells of Healthy Individuals and Neurological Patients Through Induced Pluripotency or Direct Conversion.

Stem Cells 3 Jul 2014, . Epub 3 Jul 2014
Access to healthy or diseased human neural tissue is a daunting task and represents a barrier for advancing our understanding about the cellular, genetic and molecular mechanisms underlying neurogenesis and neurodegeneration. Reprogramming of somatic cells to pluripotency by transient expression of transcription factors was achieved a few years ago. Induced pluripotent stem cells (iPSC) from both healthy individuals and patients suffering from debilitating, life-threatening neurological diseases have been differentiated into several specific neuronal subtypes. An alternative emerging approach is the direct conversion of somatic cells (i.e. fibroblasts, blood cells or glial cells) into neuron-like cells. However, to what extent neuronal direct conversion of diseased somatic cells can be achieved remains an open question. Optimization of current expansion and differentiation approaches is highly demanded to increase the differentiation efficiency of specific phenotypes of functional neurons from iPSCs or through somatic cell direct conversion. The realization of the full potential of iPSCs relies on the ability to precisely modify specific genome sequences. Genome editing technologies including zinc finger nucleases (ZFN), transcription activator-like effector nucleases (TALEN) and clustered regularly interspaced short palindromic repeat/CAS9 RNA-guided nucleases (CRISPR/CAS9) have progressed very fast over the last years. The combination of genome-editing strategies and patient-specific iPSC biology will offer a unique platform for in vitro generation of diseased and corrected neural derivatives for personalized therapies, disease modeling and drug screening. Stem Cells 2014.
More information
Martinez VG, Escoda-Ferran C, Tadeu Simões I, Arai S, Orta Mascaró M, Carreras E, Martínez-Florensa M, Yelamos J, Miyazaki T, Lozano F

The macrophage soluble receptor AIM/Api6/CD5L displays a broad pathogen recognition spectrum and is involved in early response to microbial aggression.

Cell. Mol. Immunol. Jul 2014, 11 (4) 343-54. Epub 3 Mar 2014
Apoptosis inhibitor of macrophages (AIMs), a homologue of human Spα, is a mouse soluble member of the scavenger receptor cysteine-rich superfamily (SRCR-SF). This family integrates a group of proteins expressed by innate and adaptive immune cells for which no unifying function has yet been described. Pleiotropic functions have been ascribed to AIM, from viability support in lymphocytes during thymic selection to lipid metabolism and anti-inflammatory effects in autoimmune pathologies. In the present report, the pathogen binding properties of AIM have been explored. By using a recombinant form of AIM (rAIM) expressed in mammalian cells, it is shown that this protein is able to bind and aggregate Gram-positive and Gram-negative bacteria, as well as pathogenic and saprophytic fungal species. Importantly, endogenous AIM from mouse serum also binds to microorganisms and secretion of AIM was rapidly induced in mouse spleen macrophages following exposure to conserved microbial cell wall components. Cytokine release induced by well-known bacterial and fungal Toll-like receptor (TLR) ligands on mouse splenocytes was also inhibited in the presence of rAIM. Furthermore, mouse models of pathogen-associated molecular patterns (PAMPs)-induced septic shock of bacterial and fungal origin showed that serum AIM levels changed in a time-dependent manner. Altogether, these data suggest that AIM plays a general homeostatic role by supporting innate humoral defense during pathogen aggression.
More information
Schrezenmeier H, Muus P, Socié G, Szer J, Urbano-Ispizua A, Maciejewski JP, Brodsky RA, Bessler M, Kanakura Y, Rosse W, Khursigara G, Bedrosian C, Hillmen P

Baseline characteristics and disease burden in patients in the International Paroxysmal Nocturnal Hemoglobinuria Registry.

Haematologica May 2014, 99 (5) 922-9. Epub 31 Jan 2014
Paroxysmal nocturnal hemoglobinuria is a rare, acquired disease associated with hemolytic anemia, bone marrow failure, thrombosis, and, frequently, poor quality of life. The International PNH Registry is a worldwide, observational, non-interventional study collecting safety, effectiveness, and quality-of-life data from patients with a confirmed paroxysmal nocturnal hemoglobinuria diagnosis or detectable paroxysmal nocturnal hemoglobinuria clone, irrespective of treatment. In addition to evaluating the long-term safety and effectiveness of eculizumab in a global population, the registry aims to improve diagnosis, optimize patient management and outcomes, and enhance the understanding of the natural history of paroxysmal nocturnal hemoglobinuria. Here we report the characteristics of the first 1610 patients enrolled. Median disease duration was 4.6 years. Median granulocyte paroxysmal nocturnal hemoglobinuria clone size was 68.1% (range 0.01-100%). Overall, 16% of patients had a history of thrombotic events and 14% a history of impaired renal function. Therapies included anticoagulation (31%), immunosuppression (19%), and eculizumab (25%). Frequently reported symptoms included fatigue (80%), dyspnea (64%), hemoglobinuria (62%), abdominal pain (44%), and chest pain (33%). Patients suffered from poor quality of life; 23% of patients had been hospitalized due to paroxysmal nocturnal hemoglobinuria-related complications and 17% stated that paroxysmal nocturnal hemoglobinuria was the reason they were not working or were working less. This international registry will provide an ongoing, valuable resource to further the clinical understanding of paroxysmal nocturnal hemoglobinuria.
More information
Báez A, Martín-Antonio B, Piruat JI, Barbado MV, Prats C, Alvarez-Laderas I, Carmona M, Pérez-Simón JA, Urbano-Ispizua A

Gene and miRNA Expression Profiles of Hematopoietic Progenitor Cells Vary Depending on Their Origin.

Biol. Blood Marrow Transplant. May 2014, 20 (5) 630-9. Epub 23 Jan 2014
Hematopoietic progenitor cells (HPCs) from granulocyte colony-stimulating factor (G-CSF)-mobilized peripheral blood (G-PB), bone marrow (BM), or umbilical cord blood (CB) have differing biological properties and differing kinetics of engraftment post-transplantation, which might be explained, at least in part, by differing gene and miRNA expression patterns. To assess the differences in gene and miRNA expression, we analyzed whole genome expression profiles as well as the expression of 384 miRNAs in CD34(+) cells isolated from 18 healthy individuals (6 individuals per subtype of HPC source). We identified 43 genes and 36 miRNAs differentially expressed in the various CD34(+) cell sources. We observed that CD34(+) cells from CB and BM showed similar gene and miRNA expression profiles, whereas CD34(+) cells from G-PB had a very different expression pattern. Remarkably, 20 of the differentially expressed genes are targets of the differentially expressed miRNAs. Of note, the majority of genes differentially expressed in CD34(+) cells from G-PB are involved in cell cycle regulation, promoting the process of proliferation, survival, hematopoiesis, and cell signaling, and are targets of overexpressed and underexpressed miRNAs in CD34(+) cells from the same source. These data suggest significant differences in gene and miRNA expression among the various HPC sources used in transplantation. We hypothesize that the differentially expressed genes and miRNAs involved in cell cycle and proliferation might explain the differing kinetics of engraftment observed after transplantation of hematopoietic stem cells obtained from these different sources.
More information
Bueno C, Roldan M, Anguita E, Romero-Moya D, Martín-Antonio B, Rosu-Myles M, Del Cañizo C, Campos F, García R, Gómez-Casares M, Fuster JL, Jurado M, Delgado M, Menendez P

Bone marrow mesenchymal stem cells from aplastic anemia patients preserve functional and immune properties and do not contribute to the pathogenesis of the disease.

Haematologica 11 Apr 2014, . Epub 11 Apr 2014
Aplastic anemia is a life-threatening bone marrow failure disorder characterized by peripheral pancitopenia and marrow hipoplasia. The majority of aplastic anemia cases remain idiopathic, and hematopoietic stem cell deficiency and impaired immune responses are hallmark underlying mechanisms causative for the bone marrow failure in aplastic anemia. Mesenchymal stem/stromal cells constitute an essential component of the bone marrow hematopoietic microenvironment because of their immunomodulatory properties and their ability to support hematopoiesis, and they have been involved in the pathogenesis of several hematological malignances. We have addressed whether bone marrow mesenchymal stem cells contribute, directly or indirectly, to the aplastic anemia pathogenesis. Here, we report that mesenchymal stem cell cultures can be established from the bone marrow of aplastic anemia patients and display the same phenotype and differentiation potential as their counterparts from normal bone marrow. Mesenchymal stem cells from aplastic anemia patients support the in vitro homeostasis and the in vivo repopulating function of CD34+ cells, and preserve their immunosuppressive and anti-inflammatory properties. These data demonstrates that bone marrow mesenchymal stem cells from aplastic anemia do not exert impaired functional and immunological properties, suggesting that they do not seem to contribute to the pathogenesis of the disease.
More information

Events