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Romero-Moya D.,University of Granada | Bueno C.,University of Granada | Montes R.,University of Granada | Navarro-Montero O.,University of Granada | And 6 more authors.
Haematologica | Year: 2013

The homeostasis of the hematopoietic stem/progenitor cell pool relies on a fine-tuned balance between selfrenewal, differentiation and proliferation. Recent studies have proposed that mitochondria regulate these processes. Although recent work has contributed to understanding the role of mitochondria during stem cell differentiation, it remains unclear whether the mitochondrial content/function affects human hematopoietic stem versus progenitor function. We found that mitochondrial mass correlates strongly with mitochondrial membrane potential in CD34+ hematopoietic stem/progenitor cells. We, therefore, sorted cord blood CD34+ cells on the basis of their mitochondrial mass and analyzed the in vitro homeostasis and clonogenic potential as well as the in vivo repopulating potential of CD34+ cells with high (CD34+ MitoHigh) versus low (CD34+ MitoLow) mitochondrial mass. The CD34+ MitoLow fraction contained 6-fold more CD34+CD38- primitive cells and was enriched in hematopoietic stem cell function, as demonstrated by its significantly greater hematopoietic reconstitution potential in immuno-deficient mice. In contrast, the CD34+ MitoHigh fraction was more enriched in hematopoietic progenitor function with higher in vitro clonogenic capacity. In vitro differentiation of CD34+ MitoLow cells was significantly delayed as compared to that of CD34+MitoHigh cells. The eventual complete differentiation of CD34+MitoLow cells, which coincided with a robust expansion of the CD34- differentiated progeny, was accompanied by mitochondrial adaptation, as shown by significant increases in ATP production and expression of the mitochondrial genes ND1 and COX2. In conclusion, cord blood CD34+ cells with low levels of mitochondrial mass are enriched in hematopoietic repopulating stem cell function whereas high levels of mitochondrial mass identify hematopoietic progenitors. A mitochondrial response underlies hematopoietic stem/progenitor cell differentiation and proliferation of lineagecommitted CD34- cells. © 2013 Ferrata Storti Foundation. Source

Delgado J.,Hospital Clinic | Pereira A.,Hematopathology Unit | Villamor N.,Deparment of Hemostasis and Hemotherapy | Lopez-Guillermo A.,Hospital Clinic | Rozman C.,Josep Carreras Leukemia Research Institute
Haematologica | Year: 2014

The widespread availability of statistical packages has undoubtedly helped hematologists worldwide in the analysis of their data, but has also led to the inappropriate use of statistical methods. In this article, we review some basic concepts of survival analysis and also make recommendations about how and when to perform each particular test using SPSS, Stata and R. In particular, we describe a simple way of defining cut-off points for continuous variables and the appropriate and inappropriate uses of the Kaplan-Meier method and Cox proportional hazard regression models. We also provide practical advice on how to check the proportional hazards assumption and briefly review the role of relative survival and multiple imputation. © 2014 Ferrata Storti Foundation. Source

Bueno C.,Josep Carreras Leukemia Research Institute | Roldan M.,University of Granada | Anguita E.,Servicio de Hematologia | Romero-Moya D.,Josep Carreras Leukemia Research Institute | And 11 more authors.
Haematologica | Year: 2014

Aplastic anemia is a life-threatening bone marrow failure disorder characterized by peripheral pancytopenia and marrow hypoplasia. The majority of cases of aplastic anemia remain idiopathic, although hematopoietic stem cell deficiency and impaired immune responses are hallmarks underlying the bone marrow failure in this condition. 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 hematologic malignancies. We investigated whether bone marrow mesenchymal stem cells contribute, directly or indirectly, to the pathogenesis of aplastic anemia. We found 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 maintain their immunosuppressive and anti-inflammatory properties. These data demonstrate that bone marrow mesenchymal stem cells from patients with aplastic anemia do not have impaired functional and immunological properties, suggesting that they do not contribute to the pathogenesis of the disease. © 2014 Ferrata Storti Foundation. Source

Rodriguez R.M.,Instituto Universitario Of Oncologia Del Principado Of Asturias Iuopa | Suarez-Alvarez B.,Hospital Universitario Central Of Asturias | Salvanes R.,Hospital Universitario Central Of Asturias | Huidobro C.,Instituto Universitario Of Oncologia Del Principado Of Asturias Iuopa | And 9 more authors.
Epigenetics | Year: 2014

The bromodomain and extra terminal (BET) protein family member BRD4 is a transcriptional regulator, critical for cell cycle progression and cellular viability. Here, we show that BRD4 plays an important role in embryonic stem cell (ESC) regulation. During differentiation of ESCs, BRD4 expression is upregulated and its gene promoter becomes demethylated. Disruption of BRD4 expression in ESC s did not induce spontaneous differentiation but severely diminished hematoendothelial potential. Although BRD4 regulates c-Myc expression, our data show that the role of BRD4 in hematopoietic commitment is not exclusively mediated by c-Myc. Our results indicate that BRD4 is epigenetically regulated during hematopoietic differentiation ESC s in the context of a still unknown signaling pathway. © 2014 Landes Bioscience. Source

Martinez-Trillos A.,Institute dinvestigacions Biomediques August Pi i Sunyer IDIBAPS | Pinyol M.,Unitat de Genomica | Navarro A.,Unitat de Genomica | Aymerich M.,Institute dinvestigacions Biomediques August Pi i Sunyer IDIBAPS | And 21 more authors.
Blood | Year: 2014

Mutations in Toll-like receptor (TLR ) and myeloid differentiation primary response 88 ( MYD88 ) genes have been found in chronic lymphocytic leukemia (CLL) at low frequency. We analyzed the incidence, clinicobiological characteristics, and outcome of patients with TLR/MYD88 mutations in 587 CLL patients. Twenty-three patients (3.9%) hadmutations, 19 in MYD88 (one with concurrent IRAK1 mutation), 2 TLR2 (one with concomitant TLR6 mutation), 1 IRAK1 , and 1 TLR5. No mutations were found in IRAK2 and IRAK4. TLR/MYD88- mutated CLL overexpressed genes of the nuclear factor κB pathway. Patients with TLR/MYD88 mutations were significantly younger (83% age ≤50 years) than those with no mutations. TLR/MYD88 mutations were the most frequent in youngpatients. Patients with mutated TLR/MYD88 CLLhad a higher frequency of mutated IGHV and low expression of CD38 and ZAP-70. Overall survival (OS) was better in TLR/MYD88-mutated than unmutated patients in the whole series (10-year OS, 100% vs 62%; P = .002), and in the subset of patients age ≤50 years (100% vs 70%; P = .02). In addition, relative OS of TLR/MYD88-mutated patients was similar to that in the age- and gender-matched population. In summary, TLR/MYD88 mutations identify a population of young CLL patients with favorable outcome. © 2014 by The American Society of Hematology. Source

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