ABSTRACT
INTRODUCTION: Prognosis of patients with myelodysplastic syndrome (MDS), particularly the group with lower-risk disease (LR-MDS) is very heterogeneous. Several studies have described the prognostic value of recurrent somatic mutations in MDS including all risk categories. Recently, the incorporation of genomic data to clinical parameters defined the new Molecular International Prognostic Scoring System (IPSS-M). MATERIALS AND METHODS: In this study, we evaluated the impact of molecular profile in a series of 181 patients with LR-MDS and non-proliferative chronic myelomonocytic leukemia. RESULTS: Epigenetic regulators (TET2, ASXL1) and splicing (SF3B1) were the most recurrent mutated pathways. In univariate analysis, RUNX1 or TP53 mutations correlated with lower median overall survival (OS). In contrast, SF3B1 mutation was associated with prolonged median OS [95 months (95% IC, 32-157) vs. 33 months (95% CI, 19-46) in unmutated patients (P < 0.01)]. In a multivariate Cox regression model, RUNX1 mutations independently associated with shorter OS, while SF3B1 mutation retained its favorable impact on outcome (HR: 0.24, 95% CI, 0.1-0.5; P = 0.001). In addition, TP53 or RUNX1 mutations were identified as predictive covariates for the probability of leukemic progression (P < 0.001). CONCLUSION: Incorporation of molecular testing in LR-MDS identified a subset of patients with expected poorer outcome, either due to lower survival or probability of leukemic progression.
Subject(s)
Leukemia, Myelomonocytic, Chronic , Myelodysplastic Syndromes , Humans , Core Binding Factor Alpha 2 Subunit/genetics , Myelodysplastic Syndromes/genetics , Mutation , Prognosis , Tumor Suppressor Protein p53/genetics , RNA Splicing Factors/genetics , Phosphoproteins/geneticsSubject(s)
Bone Marrow/pathology , Melanoma/diagnosis , Skin Neoplasms/diagnosis , Aged , Fatal Outcome , Humans , Male , Melanoma/secondary , Skin Neoplasms/pathologyABSTRACT
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.
Subject(s)
Bone Marrow Cells/metabolism , Fetal Blood/metabolism , Gene Expression Regulation , Genome, Human , Hematopoietic Stem Cells/metabolism , MicroRNAs/genetics , Antigens, CD34/genetics , Antigens, CD34/metabolism , Bone Marrow Cells/cytology , Cell Cycle/genetics , Cell Proliferation , Fetal Blood/cytology , Gene Expression Profiling , Hematopoietic Stem Cell Mobilization , Hematopoietic Stem Cells/cytology , Humans , MicroRNAs/metabolism , Signal TransductionABSTRACT
Granulocyte colony-stimulating factor is the most commonly used cytokine for the mobilization of hematopoietic progenitor cells from healthy donors for allogeneic stem cell transplantation. Although the administration of this cytokine is considered safe, knowledge about its long-term effects, especially in hematopoietic progenitor cells, is limited. On this background, the aim of our study was to analyze whether or not granulocyte colony-stimulating factor induces changes in gene and microRNA expression profiles in hematopoietic progenitor cells from healthy donors, and to determine whether or not these changes persist in the long-term. For this purpose, we analyzed the whole genome expression profile and the expression of 384 microRNA in CD34(+) cells isolated from peripheral blood of six healthy donors, before mobilization and at 5, 30 and 365 days after mobilization with granulocyte colony-stimulating factor. Six microRNA were differentially expressed at all time points analyzed after mobilization treatment as compared to the expression in samples obtained before exposure to the drug. In addition, 2424 genes were also differentially expressed for at least 1 year after mobilization. Of interest, 109 of these genes are targets of the differentially expressed microRNA also identified in this study. These data strongly suggest that granulocyte colony-stimulating factor modifies gene and microRNA expression profiles in hematopoietic progenitor cells from healthy donors. Remarkably, some changes are present from early time-points and persist for at least 1 year after exposure to the drug. This effect on hematopoietic progenitor cells has not been previously reported.
Subject(s)
Antigens, CD34 , Blood Donors , Gene Expression Regulation/drug effects , Granulocyte-Macrophage Colony-Stimulating Factor/pharmacology , Hematopoietic Stem Cells/metabolism , MicroRNAs/biosynthesis , Adult , Female , Gene Expression Profiling , Genome-Wide Association Study , Hematopoietic Stem Cells/cytology , Humans , Male , Time FactorsABSTRACT
ObjetivoCorrelacionar las concentraciones de factores de la coagulación (FC) con la gravedad de la enfermedad en pacientes cirróticos evaluados como candidatos a trasplante hepático. Material y métodoSe incluyó a 87 pacientes (75,9% varones) con una edad media de 54±9,4 años. La etiología y el estadio de Child-Turcotte-Pugh (CTP) fueron los siguientes: alcohol (36,8%), virus de la hepatitis C (35,6%), virus de la hepatitis B (11,5%) y otras (16,1%); A (13,8%), B (40,2%) y C (46%), respectivamente. El valor medio para el índice de Model for End-Stage Liver Disease (MELD) fue de 14,5 ± 5,9. Las concentraciones de los factores II, V, VII, VIII, IX y X se compararon entre sí para cada grado de CTP y con el índice de MELD.ResultadosCon la excepción del factor VIII, los restantes FC estaban reducidos en esta serie (particularmente los factores II, V y VII) y sus déficits estaban estrechamente relacionados con el grado de CTP, con significación estadística para el estadio C (p<0,05). También se encontró una marcada relación inversa entre el índice de MELD y los valores de los factores II, V, VII, IX y X (p<0,05).ConclusionesSe encontró relación entre las concentraciones reducidas de los factores II, V, VII, IX y X en la cirrosis hepática y la gravedad de la enfermedad(AU)
ObjetiveTo correlate blood coagulation factor levels with disease severity in cirrhotic patients evaluated as candidates for liver transplantation.Material and methodWe included 87 patients (75.9% men) with a mean age of 54±9.4 years. Etiology and Child-Turcotte-Pugh (CTP) class were as follows: alcohol-related (36.8%), hepatitis C virus infection (35.6%), hepatitis B virus infection (11.5%) and other (16.1%); class A (13.8%), class B (40.2%) and class C (46%), respectively. The mean value of the Model for End-Stage Liver Disease (MELD) score was 14.5±5.9. Levels of factors II, V, VII, VIII, IX and X were compared between each CTP grade and with the MELD score.ResultsExcept for factor VIII, all the clotting factors were reduced in our series (in particular factors II, V and VII) and deficiencies in these factors were closely related to CTP grade with statistical significance for stage C (p<0.05). We also found a marked inverse correlation between the MELD score and factors II, V, VII, IX and X values (p<0.05).ConclusionsA correlation was found between reduced levels of factors II, V, VII, IX and X in liver cirrhosis and the severity of liver disease(AU)
Subject(s)
Humans , Liver Diseases/surgery , Liver Transplantation , Preoperative Care , Blood Coagulation Factors/analysis , Chronic Disease , Severity of Illness IndexABSTRACT
OBJECTIVE: To correlate blood coagulation factor levels with disease severity in cirrhotic patients evaluated as candidates for liver transplantation. MATERIAL AND METHOD: We included 87 patients (75.9% men) with a mean age of 54+/-9.4 years. Etiology and Child-Turcotte-Pugh (CTP) class were as follows: alcohol-related (36.8%), hepatitis C virus infection (35.6%), hepatitis B virus infection (11.5%) and other (16.1%); class A (13.8%), class B (40.2%) and class C (46%), respectively. The mean value of the Model for End-Stage Liver Disease (MELD) score was 14.5+/-5.9. Levels of factors II, V, VII, VIII, IX and X were compared between each CTP grade and with the MELD score. RESULTS: Except for factor VIII, all the clotting factors were reduced in our series (in particular factors II, V and VII) and deficiencies in these factors were closely related to CTP grade with statistical significance for stage C (p <0.05). We also found a marked inverse correlation between the MELD score and factors II, V, VII, IX and X values (p <0.05). CONCLUSIONS: A correlation was found between reduced levels of factors II, V, VII, IX and X in liver cirrhosis and the severity of liver disease.