[Show abstract][Hide abstract] ABSTRACT: Abstract The impaired hematopoiesis in acquired aplastic anemia (AA) results from immune-mediated mechanisms. We characterized polymorphisms implicated in controlling type-1 cytokine production in 69 AA patients. Our data suggest that the studied polymorphisms are not associated with susceptibility in the overall AA population. However, the presence of the higher expressing TNF -308A allele was associated with younger age (p=0.0297), more profound neutropenia (p=0.0312), and over-represented in very severe AA patients (p=0.0168). The higher producing IFNG 12 CA-repeat allele showed a strong linkage disequilibrium with +874T allele, and was associated with lower hemoglobin level (p=0.0351). Also, the presence of at least one higher expressing variant was more frequent among responder patients to immunosuppressive treatment (p=0.0519). Our findings suggest that the presence of higher expressing variants of TNF-α and IFN-γ in AA patient's genotypes would be related to clinical parameters, disease severity and therapy outcomes.
No preview · Article · Sep 2014 · Leukemia and Lymphoma
[Show abstract][Hide abstract] ABSTRACT: One of the most challenging problems in hematology is the heterogeneous group of disorders that were formally defined as Myelodysplastic Syndromes (MDS) by the French-American-British Cooperative Group in 1982. MDS are clonal disorders of hematopoietic stem cells with a propensity to leukemic evolution. Idiopathic MDS occur mainly in older persons with an incidence of 5 per 100,000 persons per year in the general population that increases to 20 to 50 per year after 60 years of age. The bone marrow is normo/hiper-cellular, displays various morphologic abnormalities and the stem cells show defective capacity for self-renewal and differentiation leading into an ineffective hematopoiesis. Most patients are initially asymptomatic, and their condition is incidentally discovered on a routine blood test. Approximately 80% of patients manifests with anemia at diagnosis, and this percentage is increased in parallel with the evolution of the disease, being one of the hallmarks. The anemia is frequently macrocytic but refractory to treatment with folate and vitamin B12. The clinical course of MDS is highly variable, ranging from stable disease over 10 years to death within a few months due to complications associated with their cytopenias or leukemic transformation. Since the development of the Bournemouth index in 1985, various scoring systems have been designed, based on clinical characteristic at presentation, in order to define prognostic subgroups. Anemia is well established as a negative prognostic factor. The International Prognostic Scoring System, the gold standard for risk assessment, has been recently revised (IPSS-R) where new clinical relevant cut-points for hemoglobin level were defined, among other changes. In our series of 578 (324 patients belong to the Argentinean MDS Registry) de novo MDS patients, the degree of anemia shows a good reproducibility and effectiveness to predict clinical outcome. Patients were distributed according to the IPSS-R cut-points for hemoglobin level into: 256 (44%) ≥10 g/dL, 191 (33%) 8-9.9 g/dL and 131 (23%) < 8 g/dL, with median survival of 60, 35, and 19 months, and time to leukemic evolution (25% of patients) of 66, 23 and 14 months, respectively (p < 0.001). The relationship between severe anemia and poor clinical outcome suggests that anemia initiates or exacerbates functional decline, particularly, involving cardiovascular disease which is one of the most common co-morbidity in MDS patients. Also, there is a high prevalence of patients with transfusion dependence who are prompt to develop secondary iron overload, associated with clinical organ dysfunction, increased risk of cardiac failure, and reduced survival. The great variability in the outcome of MDS complicates decisionmaking regarding therapies and prognostic characterization of individual patients is vital prior initiating treatment. The main objective in lower risk patients is improving the quality of life, and in higher risk patients is to extend the survival trying to modify the natural history of the disease. Accordingly, therapies vary from supportive care to intensive chemotherapy and stem cell transplantation. The degree of anemia is one of the major criterions for diagnosis, prognosis and to proper select type and timing of treatment in MDS patients.
[Show abstract][Hide abstract] ABSTRACT: Cytokines play important roles in the regulation of hematopoiesis, and a fine balance between the actions of stimulatory/ myelosuppressive factors is required for optimal production of cells of different hematopoietic lineages. Tumor Necrosis Factor-alpha (TNF ) is a multifunctional proinflammatory cytokine that has been shown to strongly inhibit hematopoiesis and has been implicated in the pathogenesis and phenotypes of Myelodysplastic Syndromes (MDS). MDS are a heterogeneous group of clonal hematopoietic stem cell disorders characterized by ineffective hematopoiesis, multilineage dysplasia, peripheral cytopenia(s), and susceptibility to leukemia. The phenotypic diversity of MDS may be the consequence of a dynamic balance among the marrow microenvironment, proliferation capacity of the abnormal clone and intensity of the immune attack towards the marrow. The ineffective hematopoiesis is accompanied by an extensive apoptotic cellular death of myeloid precursors at the beginning of the disease. The bone marrow microenvironment may interact with MDS clone to create an adverse proinflammatory cytokine background associated with increased apoptotic levels. However, molecular mechanisms involved in this aberrant cytokine generation are not known. The regulatory and coding regions of cytokine genes are relatively polymorphic including a significant number of single nucleotide polymorphisms (SNPs), some of which are known to modify cytokine activity. TNF gene, located at 6p21.3, contains in its promoter region the -308G/A SNP and the -308A variant has been associated with an increased transcription and production of this cytokine. Therefore, the aim of our work was to study the -308G/A TNF SNP and to analyze whether the presence of the high producing variant is associated with clinical parameters in a cohort of 132 Argentine de novo MDS patients. We found that the A/A+G/A genotype was overrepresented 2-fold in our population (p=0.020, odds ratio-OR: 2.122) and these differences were more evident in the refractory anemia subtype (p=0.004, OR: 2.855). The presence of the high expressing -308A allele was associated with younger age (57 ± 17 vs. 65 ± 14 years, p=0.017), higher risk to present with hemoglobin levels less than 7g/dL (29% vs. 8%, p=0.002, OR: 4.688) and platelet counts less than 50000/μL (38% vs. 18%, p=0.021, OR: 2.788) at diagnosis. Also, these patients showed 3.2-fold higher risk of transfusion requirement (77% vs. 52%, p=0.012, OR: 3.205) during the follow up. In conclusion, the presence of an inherited -308A TNF, which increases the transcription level of this proinflammatory cytokine, was associated with more profound cytopenias and the necessity of transfusion requirement in our cohort of MDS patients. This immunogenetic background may influence the bone marrow microenviroment that cooperates with intrinsic defects of MDS progenitors to increase the severity of certain phenotypic features of the disease.
[Show abstract][Hide abstract] ABSTRACT: Myelodysplastic syndromes (MDS) are a heterogeneous group of clonal hematological diseases characterized by refractory cytopenia(s) as a result of ineffective hematopoiesis, in the context of a mostly normo/hypercellular bone marrow (BM), with variable risk of progression to acute myeloid leukemia (AML). Similar to most malignancies, MDS likely arise from a genetically transformed primitive hematopoietic stem cell, while subsequent genetic and epigenetic changes contribute to their development and progression. Immune, cytokine and stromal responses in the host are important to define the disease phenotype. Approximately 50% of patients show abnormal karyotype not associated with any particular chromosomal alteration. They are most often characterized by total or partial loss of material from chromosomes 5, 7, 13, 17, 20 or a sex chromosome, as well as a relatively high incidence of genetic gains such as trisomy 8, 19 and 21, while recurrent translocations or other structural abnormalities are less common. The great variability in the natural history of MDS complicates decision-making regarding therapies, and the inclusion of cytogenetic findings into different prognostic systems has contributed to improvement in prognostic assessment. Karyotype has been recognized as an independent prognostic factor in MDS since 1993 when the Lille system confirmed that the presence of complex karyotype was associated with a poor prognosis. In 1997, the International prognostic scoring system (IPSS) recognized three cytogenetic risk groups where some particular alterations (-Y, 5q-, -7/7q-, +8 and 20q-) were associated with a specific prognosis, thus cytogenetics becoming a widely accepted tool to assess prognosis. However, the IPSS included in the intermediate group a number of low frequency cytogenetic alterations that make it heterogeneous and is still a matter of debate. Later on, the IPSS was revised and the risk of some less frequent cytogenetic abnormalities (i.e. rearr3q, 11q-, 12p-, i17q, +19 and +21) was specified, splitting cytogenetics into five categories (IPSS-R). Recently, we have developed an alternative but complementary strategy to the original IPSS, where isolated deletions, excluding 7q-, were placed into good prognostic findings and monosomal karyotypes (MK) among the worse ones (IPSS-MK). New published data have confirmed the unfavorable prognosis associated with MK in, not only AML, but also MDS. This chapter thus focuses on the cytogenetic profile of MDS describing clinical, molecular background and prognostic relevance of chromosome findings. We also review different cytogenetic risk stratifications that have been published during the past twenty years since the karyotype was first recognized as an independent factor for predicting prognosis in MDS.
[Show abstract][Hide abstract] ABSTRACT: Myelodysplastic Syndromes (MDS) are a heterogeneous group of hematological diseases characterized by refractory cytopenia(s) and variable risk
of leukemic progression. Cytogenetic analysis is important in day-to-day clinical practice helping to define subgroups of MDS patients who share
similarities in the course of the disease. There are recurring aberrations affecting chromosomes 5, 7, 8, and 20. While all of them do not suggest a
therapeutic approach, their presence has been considered as a risk indicator since the original international prognostic scoring system (IPSS) was
published. The most recent cytogenetic stratifications tried to find the prognostic significance of less frequent alterations which have been longer
included in the intermediate group. Moreover, monitoring of karyotype changes is suggested to evaluate cytogenetic response to treatments and the
acquisition of new aberrations associated to an unfavorable outcome. This review focuses on different cytogenetic risk stratifications that have been
published during the past twenty years and the molecular background of the most relevant chromosomal findings.
[Show abstract][Hide abstract] ABSTRACT: Myelodysplastic syndromes (MDS) constitute a heterogeneous group of clonal hematological diseases characterized by refractory cytopenia(s). MDS patients show increased levels of tumor necrosis factor alpha (TNFα) which is a multifunctional proinflammatory cytokine. The aim of this work is to examine the presence of -308A/G TNFα variants and to analyze whether it is associated with clinical parameters in a cohort of 101 Argentinean de novo MDS patients. The A/A+A/G genotype at TNFα -308 was overrepresented 2-fold in our population (p=0.0499, odds ratio-OR: 2.107) and these differences were more evident in RA-FAB subtype (p=0.0424, OR: 2.502). The presence of the high expressing -308A allele was associated with lower hemoglobin level (8.3 vs 9.9g/dL; p=0.0206), reduced platelet counts (89,000 vs 130,000/μL; p=0.0381) and younger age (59 vs 68years; p=0.0122) at diagnosis. Also, these patients showed 3.8-fold higher risk of transfusion requirement (76% vs 46%, p=0.0105) during the follow up. In conclusion, the presence of an inherited -308A TNFα, which increases its transcription level, was associated with the MDS phenotype in our cohort of Argentine MDS patients. Also, an overexpression of TNFα may promote an underlying proinflammatory state that cooperates with intrinsic defects within MDS progenitors to increase the severity of certain phenotypic features of the disease.
Full-text · Article · Dec 2011 · Blood Cells Molecules and Diseases