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1.
Front Immunol ; 15: 1427810, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39351227

RESUMO

It has been demonstrated previously that human leukocyte antigen class I (HLA-I) and class II (HLA-II) alleles may modulate JAK2 V617F and CALR mutation (CALRmut)-associated oncogenesis in myeloproliferative neoplasms (MPNs). However, the role of immunogenetic factors in MPNs remains underexplored. We aimed to investigate the potential involvement of HLA genes in CALRmut+ MPNs. High-resolution genotyping of HLA-I and -II loci was conducted in 42 CALRmut+ and 158 JAK2 V617F+ MPN patients and 1,083 healthy controls. A global analysis of the diversity of HLA-I genotypes revealed no significant differences between CALRmut+ patients and controls. However, one HLA-I allele (C*06:02) showed an inverse correlation with presence of CALR mutation. A meta-analysis across independent cohorts and healthy individuals from the 1000 Genomes Project confirmed an inverse correlation between the presentation capabilities of the HLA-I loci for JAK2 V617F and CALRmut-derived peptides in both patients and healthy individuals. scRNA-Seq analysis revealed low expression of TAP1 and CIITA genes in CALRmut+ hematopoietic stem and progenitor cells. In conclusion, the HLA-I genotype differentially restricts JAK2 V617F and CALRmut-driven oncogenesis potentially explaining the mutual exclusivity of the two mutations and differences in their presentation latency. These findings have practical implications for the development of neoantigen-based vaccines in MPNs.


Assuntos
Calreticulina , Genótipo , Janus Quinase 2 , Mutação , Transtornos Mieloproliferativos , Humanos , Janus Quinase 2/genética , Calreticulina/genética , Transtornos Mieloproliferativos/genética , Transtornos Mieloproliferativos/imunologia , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Adulto , Carcinogênese/genética , Alelos , Antígenos de Histocompatibilidade Classe I/genética , Idoso de 80 Anos ou mais
2.
Front Oncol ; 14: 1410656, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39156702

RESUMO

Myelodysplastic syndromes (MDS) are a group of malignant clonal hematological disorders with heterogeneous clinical course and risk of transformation to acute myeloid leukemia. Genetic and epigenetic dysregulation, including alterations in microRNA (miRNA) expression, plays a pivotal role in MDS pathogenesis influencing disease development and progression. MiRNAs, known for their regulatory roles in gene expression, have emerged as promising biomarkers in various malignant diseases. This review aims to explore the diagnostic and prognostic roles of miRNAs in MDS. We discuss research efforts aimed at understanding the clinical utility of miRNAs in MDS management. MiRNA dysregulation is linked to specific chromosomal abnormalities in MDS, providing insights into the molecular landscape of the disease. Circulating miRNAs in plasma offer a less invasive avenue for diagnostic and prognostic assessment, with distinct miRNA profiles identified in MDS patients. Additionally, we discuss investigations concerning the role of miRNAs as markers for treatment response to hypomethylating and immunomodulating agents, which could lead to improved treatment decision-making and monitoring. Despite significant progress, further research in larger patient cohorts is needed to fully elucidate the role of miRNAs in MDS pathogenesis and refine personalized approaches to patient care.

3.
Clin Lymphoma Myeloma Leuk ; 24(6): e267-e275.e2, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38490927

RESUMO

BACKGROUND: Melflufen, a first-in-class alkylating peptide-drug conjugate, rapidly enters tumor cells and metabolizes to melphalan. In previous studies, melflufen was administered via central venous catheter (CVC). However, administration by peripheral venous catheter (PVC) may be preferable. PATIENTS AND METHODS: PORT was a two-period, phase 2 crossover study of CVC versus PVC melflufen administration in patients with relapsed/refractory multiple myeloma. Adults with ≥ 2 prior therapies refractory to/intolerant of an immunomodulatory drug and a proteasome inhibitor were randomized 1:1 to weekly oral dexamethasone plus melflufen (40 mg) via CVC or PVC infusion on day 1 of 28-day cycle 1. In cycle 2, patients continued dexamethasone and crossed over to the other melflufen administration route. In cycle 3, all patients received melflufen until progression; PVC or CVC routes were allowed based upon investigator decision. Pharmacokinetic sampling was performed during and after melflufen infusion. Primary endpoints were melphalan pharmacokinetic parameters (Cmax, AUC(0-t), and AUC(0-∞)) and frequency and severity of PVC-related local reactions. RESULTS: The 90% CIs for adjusted geometric mean ratios for pharmacokinetic parameters following CVC versus PVC administration were within the 0.8-1.25 bioequivalence range (Cmax 0.946 [90% CI: 0.849, 1.053]; AUC(0-t) 0.952 [90% CI: 0.861, 1.053]; AUC(0-∞) 0.955 [90% CI: 0.863, 1.058]). In both arms, adverse events were primarily hematological and similar; no phlebitis or local infusion-related reactions occurred. CONCLUSION: Melflufen PVC and CVC administrations are bioequivalent based on melphalan pharmacokinetic parameters. Melflufen via PVC was well tolerated, with no infusion-related reactions or new safety signals and may represent an alternative route of administration.


Assuntos
Estudos Cross-Over , Mieloma Múltiplo , Humanos , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/patologia , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Fenilalanina/análogos & derivados , Fenilalanina/administração & dosagem , Fenilalanina/farmacocinética , Adulto , Melfalan/administração & dosagem , Melfalan/uso terapêutico , Melfalan/análogos & derivados , Recidiva Local de Neoplasia/tratamento farmacológico , Administração Intravenosa , Idoso de 80 Anos ou mais , Resultado do Tratamento , Infusões Intravenosas
4.
Rom J Intern Med ; 62(1): 44-51, 2024 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-37948316

RESUMO

INTRODUCTION: This study aimed to assess the effectiveness of multiplex ligase-dependent probe amplification (MLPA) in the initial genetic screening of patients with acute myeloid leukemia (AML) since current risk stratification and clinical management depend on molecular-genetic markers. METHODS: We performed a prospective case-control study on newly diagnosed patients from the Clinical hematology clinic of UMHAT "St. Marina", Varna, for the period 02.2022 - 02.2023. MLPA - a semiquantitative PCR-based method, was implemented with probes for 40 AML/myelodysplastic syndrome-typical genetic changes. We compared these findings with a parallelly carried out cytogenetic analysis, part of the routine diagnostic process. RESULTS: We assessed 61 patients - 29 females and 32 males, median age of 61 years for females and 65 for males (min-max 20-89). 34 (56%) of all showed pathological results, while the rest 27 (44%) did not. Of the 34, 22 (65%) had a single gene variant in genes NPM1, DNMT3A, FLT3, and IDH2, isolated or in combination. 18 (53%) of the same 34 also had copy number aberration (CNA) in chromosomes 4, 5, 6, 7, 11, 14, 17, and 21. The latter were either isolated or in combination with other findings. 8 of the 18 cases also underwent cytogenetic analysis, with concordance between the two methods in 4. CONCLUSION: MLPA is an informative method for initial genetic assessment in addition to cytogenetic analysis. Still, more patients are needed to draw finite conclusions on its eligibility for routine use. Given the significant percentage of normal results - 44%, simultaneous evaluation of more genetic markers, included in current guidelines, is reasonable.


Assuntos
Leucemia Mieloide Aguda , Nucleofosmina , Masculino , Feminino , Humanos , Pessoa de Meia-Idade , Mutação , Estudos de Casos e Controles , Marcadores Genéticos , Testes Genéticos , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/genética , Prognóstico
5.
Cancers (Basel) ; 15(23)2023 Nov 24.
Artigo em Inglês | MEDLINE | ID: mdl-38067265

RESUMO

The hallmark of multiple myeloma is myeloma related bone disease. Interactions between myeloma plasma cells (MPCs), stromal cells, and the bone marrow (BM) microenvironment play a critical role in the pathogenesis of MBD. Bone remodeling is severely dysregulated with the prevalence of osteoclast activity. We aimed to assess circulating levels of sRANKL, periostin, and osteopontin as osteoclast activators in NDMM patients at diagnosis and in the course of treatment, correlations with clinical and laboratory data, and to evaluate their potential as additional biomarkers for the assessment of MBD. The current study involved 74 subjects (41 NDMM patients, 33 controls). MBD was assessed by whole-body low-dose computed tomography. sRANKL, periostin, and osteopontin were assayed by commercial ELISA kits. At diagnosis, all tested parameters were significantly higher in NDMM patients compared to the controls (p < 0.0001), correlating with disease stage, MBD grade, and BM infiltration by MPCs. During therapy, the serum levels of all tested proteins decrease, most prominently after autologous stem cell transplantation (p < 0.0001). A significant reduction was established in patients achieving complete and very-good partial response compared to all others (p < 0.05). In conclusion, sRANKL, periostin, and osteopontin reflect MBD severity and could be promising markers for MBD monitoring and the effect of myeloma treatment.

6.
Med Mycol Case Rep ; 42: 100613, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-37867574

RESUMO

Invasive fungal infections are common complication in hematopoietic stem cell transplant recipients, often leading to high morbidity and mortality rates. Furthermore, when invasive fungal co-infections are diagnosed the prognosis is rarely favorable. Here, we present a rare case of a 47-year-old HIV-negative male with invasive pulmonary co-infection caused by Aspergillus sp. and Pneumocystis jirovecii, complicated by Cytomegalovirus reactivation following second allogeneic hematopoietic stem cell transplantation with a fatal outcome. 2012 Elsevier Ltd. All rights reserved.

7.
J Clin Med ; 12(13)2023 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-37445475

RESUMO

Dickkopf-1 (DKK-1) and sclerostin are essential Wnt/ß-catenin pathway inhibitors, playing an important role in multiple myeloma bone disease (MBD). We aimed to examine the serum DKK-1 and sclerostin variations in newly diagnosed multiple myeloma (NDMM) patients at diagnosis and in the course of therapy, including autologous stem cell transplantation (ASCT). This study included 41 NDMM-patients and 33 controls. MBD was assessed by whole-body low-dose computed tomography. DKK-1 and sclerostin were assayed by commercial ELISA kits. At diagnosis, NDMM-patients revealed significantly higher DKK-1 and sclerostin values (p < 0.0001), showing dependence on disease stage (lowest in ISS-I and highest in ISS-III: p < 0.0012 and p < 0.025, respectively, for both proteins). Bone lesions revealed significant positive correlation with both DKK-1 (p < 0.05) and sclerostin (p < 0.0001). In the course of therapy, significant reduction, more prominent after ASCT, was observed for both parameters in each treatment point compared to the baseline (p < 0.0001). Markedly lower sclerostin (p < 0.01) and DKK-1 (p < 0.05) values were observed in patients with complete and very good partial response compared to those with partial response, stable, or progressive disease. Sclerostin and DKK-1 in NDMM patients reflect the MBD severity and the effect of therapy. Both proteins could represent a novel tool for better disease monitoring and effectiveness of therapy.

8.
Indian J Hematol Blood Transfus ; : 1-5, 2023 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-37362402

RESUMO

The bloodstream infections (BSIs) are among the most common infectious complications after hematopoietic stem-cell transplantation (HSCT), often associated with high mortality rates. The aim of this study was to evaluate the incidence, risk factors and outcome of BSIs in HSCT recipients from the Transplantation Center of the University Hospital in Varna, Bulgaria during the period January 2019-December 2021. The role of patient- and transplantation-related variables was studied as potential risk factors for BSIs and survival after HSCT. Seventy-four patients were included in the study. The cumulative incidence of BSIs was 35%. The mean period of BSI onset after HSCT was 8 days. The Gram-positive bacteria were more commonly isolated as causative agents (52.3%). The mortality rate 30 days after the diagnosis of BSI was 23%. Fecal colonization with multidrug-resistant (MDR) bacteria (p = 0.005) and pre-transplant BSI (p = 0.05) were associated with significantly increased risk for post-HSCT BSIs. The overall 4-month survival was 86.5%. A statistical significance was found between the type of the underlying disease (acute leukemia and lymphoma, p = 0.043), previous HSCT (p = 0.001) and 4-month survival. This study confirms that the fecal colonization with MDR bacteria before transplantation and pre-transplant BSIs are independent risk factors for the occurrence of BSI in the early period after HSCT. Pre- and posttransplant monitoring of the patient fecal colonization status with MDR organisms, could contribute considerably to the prevention and successful management of the infectious complications in patients after HSCT.

9.
Rom J Intern Med ; 60(2): 103-114, 2022 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-35182066

RESUMO

Acute myelogenous leukemia is a multi-step hematological malignancy, affecting function, growth, proliferation and cell cycle of myeloid precursors. Overall assessment of patients with the disease requires among everything else, a comprehensive investigation of the genetic basis through various methods such as cytogenetic and molecular-genetic ones. This clarification provides diagnostic refinement and carries prognostic and predictive value in respect of essential therapeutic choices.With this review of the literature, we focus on summarizing the latest recommendations and preferred genetic methods, as well as on emphasizing on their general benefits and limitations. Since none of these methods is actually totipotent, we also aim to shed light over the often-difficult choice of appropriate genetic analyses.


Assuntos
Leucemia Mieloide Aguda , Humanos , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/terapia , Prognóstico
10.
Case Rep Hematol ; 2021: 1717506, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34136291

RESUMO

Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph + ALL) is an aggressive disease with poor outcomes. Despite the incorporation of tyrosine kinase inhibitors (TKIs) in the therapeutic strategies, patients who relapse after chemotherapy plus TKI have poor overall survival (OS) and less chance to proceed to hematopoietic stem cell transplantation (HSCT) which remains the only curative approach. Therefore, new drugs, such as antibody-targeted therapies alone or in combination with TKIs, offer new therapeutic options for those patients. However, the combination of inotuzumab plus ponatinib has limited application. We present a case of a patient affected by Ph + ALL with T315I mutation successfully treated after early relapse with inotuzumab plus ponatinib, followed by allogeneic HSCT and ponatinib maintenance.

11.
Folia Med (Plovdiv) ; 63(6): 941-947, 2021 Dec 31.
Artigo em Inglês | MEDLINE | ID: mdl-35851227

RESUMO

AIM: The aim of this study was to evaluate the clinical significance of Aspergillus Galactomannan antigen (GM) test for the diagnosis of invasive pulmonary aspergillosis (IPA) in patient with hematological malignancies, including patients undergoing hematopoietic stem cell transplantation (HSCT). MATERIALS AND METHODS: Between January 2016 and June 2019, ninety patients were tested for GM. A total of 134 blood and 19 bronchoalveolar lavage (BAL) samples were analyzed using Platelia Aspergillus Ag Enzyme-Immuno Assay (Bio-Rad Laboratories). The median age of patients was 63 years (range 25-81). Fifty-six patients (62.2%) were male. All patients were allocated into five groups on the basis of their GM results. RESULTS: A positive GM antigen test was detected in 16 patients (17.7%). Of these, ten had positive serum samples (group I). After re-testing, 1 patient from group I gave a negative result. Five patients with negative serum samples gave positive BAL results (group II). One patient had positive both serum and BAL samples (group III). Fifteen GM positive patients (9 from group I, group II, and III) were categorized as probable IPA. Thirty-six patients (40%) negative for GM (group IV) were considered with a possible IPA. IPA was excluded in 38 patients (42.2%) (group V). Anti-mould therapy was initiated in all 15 patients who were considered to be cases with probable IPA. IPA was the immediate cause of death in 3 cases (25%). CONCLUSIONS: Our results demonstrated the clinical applicability of the GM test for screening of IPA in high-risk patients with hematological malignancies and HSCT.


Assuntos
Neoplasias Hematológicas , Transplante de Células-Tronco Hematopoéticas , Aspergilose Pulmonar Invasiva , Adulto , Idoso , Idoso de 80 Anos ou mais , Líquido da Lavagem Broncoalveolar , Feminino , Neoplasias Hematológicas/complicações , Neoplasias Hematológicas/terapia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Aspergilose Pulmonar Invasiva/diagnóstico , Aspergilose Pulmonar Invasiva/tratamento farmacológico , Aspergilose Pulmonar Invasiva/etiologia , Masculino , Pessoa de Meia-Idade , Sensibilidade e Especificidade
12.
Nucl Med Rev Cent East Eur ; 19(B): 11-13, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27813622

RESUMO

Extranodal lymphoma, secondary to or accompanying nodal disease is uncommon, but not unusual finding. 18-Fluorodeoxyglucose positron emission tomography (18F-FDG PET/CT) imaging has an essential role in the staging of lymphoma, in treatment response monitoring, and in detection of recurrence. We present a case of a 52-year-old man with generalized diffuse large B-cell lymphoma (DLBCL) with multiple extranodal sites involvement detected by 18F-FDG PET/CT. With this clinical case we demonstrate that 18F-FDG PET-CT is a more effective technique than CE-CT for the evaluation of viable extranodal involvement of the diffuse large B-cell lymphoma (DLBCL) and should be combined in the monitoring of DLBCL.


Assuntos
Linfoma Difuso de Grandes Células B/diagnóstico por imagem , Recidiva Local de Neoplasia/diagnóstico por imagem , Fluordesoxiglucose F18 , Humanos , Linfoma Difuso de Grandes Células B/patologia , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/patologia , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Compostos Radiofarmacêuticos
13.
J Cell Biochem ; 101(2): 331-47, 2007 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-17177294

RESUMO

Focal adhesion kinase (FAK) and its downstream signaling targets are implicated in the process of apoptosis induced by external stimuli, in several mammalian systems. In this report, we demonstrate, that medfly (Ceratitis capitata) hemocytes do undergo apoptosis during larval development. In particular, we show using Western blot, ELISA and flow cytometry analysis, that FAK expression silencing in transfected by FAK double-stranded RNA (dsRNA) hemocytes, enhances twofold hemocyte apoptosis, by signaling through Src, MEK/ERK, and PI-3K/Akt signaling pathways. FAK expression silencing, in response to FAK dsRNA treatment, blocks partially the phosphorylation of its downstream targets. Pre-incubation of hemocytes, with specific inhibitors of FAK downstream signaling molecules, demonstrated that all these inhibitors reduced hemocyte viability and enhanced the magnitude of apoptosis about threefold. This data suggest that these pathways contribute to hemocyte survival and/or death during development. The expression and phosphorylation of FAK, Src, PI-3K p85a, Akt, and ERK signaling molecules appear to be dependent upon developmental stages. The expression and phosphorylation of the above signaling molecules, in annexin-positive and annexin-negative hemocytes is also distinct. The maximum expression and phosphorylation of FAK, Src, PI-3K p85a, Akt, and ERK appeared in annexin-positive hemocytes, in both early and late apoptotic hemocytes. The novel aspect of this report is based on the fact that hemocytes attempt to suppress apoptosis, by increasing the expression/phosphorylation of FAK and, hence its downstream targets signaling molecules Src, ERK, PI-3K p85a, and Akt. Evidently, the basic survival pathways among insects and mammals appear to remain unchanged, during evolution.


Assuntos
Apoptose/fisiologia , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Quinase 1 de Adesão Focal/metabolismo , Hemócitos/fisiologia , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/fisiologia , Quinases da Família src/metabolismo , Animais , Anexinas/metabolismo , Sobrevivência Celular , Ceratitis capitata/citologia , Ceratitis capitata/embriologia , Ceratitis capitata/metabolismo , Quinase 1 de Adesão Focal/genética , Inativação Gênica , Hemócitos/citologia , Humanos , Proteínas de Insetos/genética , Proteínas de Insetos/metabolismo , Fosforilação , RNA de Cadeia Dupla/metabolismo
14.
Haematologica ; 91(12): 1714-6, 2006 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-17145614

RESUMO

We determined the intracellular expression and inducibility of heat shock proteins (Hsps) 72, 73 and 27 in the bone marrow of patients with myelodysplastic syndrome (MDS) and controls. Hsps were overexpressed in MDS marrow especially in advanced disease, providing resistance to induction of apoptosis. These data suggest that Hsps could be implicated in the progression of MDS to acute myeloid leukemia.


Assuntos
Medula Óssea/metabolismo , Regulação Neoplásica da Expressão Gênica/fisiologia , Proteínas de Choque Térmico/biossíntese , Proteínas de Choque Térmico/genética , Síndromes Mielodisplásicas/metabolismo , Medula Óssea/patologia , Progressão da Doença , Humanos , Síndromes Mielodisplásicas/genética , Síndromes Mielodisplásicas/patologia
15.
Clin Immunol ; 113(3): 310-7, 2004 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-15507396

RESUMO

Myelodysplastic syndromes (MDS) are clonal stem cell disorders, characterized by ineffective and dysplastic hematopoiesis. MDS patients have a defective immune response manifested by increased susceptibility to bacterial infections, autoimmune phenomena, and high incidence of lymphoid malignancies. Presently, we investigated the phenotype and function of monocyte-derived dendritic cells (MoDC) in 23 MDS patients and 15 controls at different stages of differentiation using the maturation stimuli tumor necrosis factor-alpha (TNF-alpha) and LPS. Monocytes from MDS patients showed low potential to differentiate into dendritic cells (DC), as determined by low cell yield and CD1a expression. MDS-MoDCs exhibited low expression of mannose receptor and reduced endocytic capacity. MDS-MoDCs showed a diminished response to TNF-alpha with low CD83, CD80, and CD54 expression and allostimulatory capacity. In patients with 5q syndrome, monocytes and MoDCs were positive for the 5q deletion, suggesting their origin from the malignant clone. Our data indicate that MoDCs in MDS display quantitative and functional abnormalities that may contribute to the defective immune response of these patients.


Assuntos
Diferenciação Celular/efeitos dos fármacos , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/patologia , Monócitos/efeitos dos fármacos , Monócitos/patologia , Síndromes Mielodisplásicas/patologia , Fator de Necrose Tumoral alfa/farmacologia , Idoso , Idoso de 80 Anos ou mais , Antígenos/metabolismo , Células Cultivadas , Células Dendríticas/metabolismo , Endocitose , Feminino , Citometria de Fluxo , Humanos , Lectinas Tipo C/metabolismo , Masculino , Receptor de Manose , Lectinas de Ligação a Manose/metabolismo , Pessoa de Meia-Idade , Monócitos/metabolismo , Fenótipo , Receptores de Superfície Celular/metabolismo
16.
Br J Haematol ; 126(6): 806-14, 2004 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-15352984

RESUMO

Myelodysplastic syndrome (MDS) is a stem cell disorder characterized by ineffective haematopoiesis and blood cytopenias. The present study investigated the potential of bone marrow CD34(+) progenitors in MDS patients to proliferate and differentiate into dendritic cells (DCs) in a cytokine-supplemented liquid culture system and analysed the status of blood DC subsets in these patients. CD34(+) progenitors had low potential to generate DCs in vitro, as the number of DCs obtained from one CD34(+) cell was significantly lower compared with controls (median value 0.2 vs. 4, P = 0.003). In patients, the survival and proliferation of CD34(+) cells in culture was not correlated to the degree of apoptosis. Phenotypically and functionally CD34(+)-derived DCs were similar in MDS patients and normal subjects. The percentage of both circulating DC subsets in patients was extremely diminished compared with controls (myeloid DC: 0.10 +/- 0.10% vs. 0.35 +/- 0.13%, P < 0.001; plasmacytoid DC: 0.11 +/- 0.10% vs. 0.37 +/- 0.14%, P < 0.001). In cases with the 5q deletion both CD34-derived DCs and blood DCs harboured the cytogenetic abnormality. Our results indicate that, in MDS, the production of DCs is affected by the neoplastic process resulting in ineffective 'dendritopoiesis' with low blood DC precursor numbers. This quantitative DC defect probably contributes to the poor immune response against infectious agents and to the escape of the malignant clone from immune recognition with disease progression towards acute leukaemia.


Assuntos
Antígenos CD34/análise , Células Dendríticas/patologia , Células-Tronco Hematopoéticas/patologia , Síndromes Mielodisplásicas/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Apoptose , Diferenciação Celular , Divisão Celular , Células Cultivadas , Células Clonais/patologia , Células Dendríticas/imunologia , Feminino , Células-Tronco Hematopoéticas/imunologia , Humanos , Imunofenotipagem , Teste de Cultura Mista de Linfócitos , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/sangue , Síndromes Mielodisplásicas/imunologia
17.
Leuk Res ; 28(8): 805-12, 2004 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-15203278

RESUMO

Excessive intramedullary apoptosis has been considered to account for the paradox of hypercellular marrow and refractory cytopenias in myelodysplastic syndrome (MDS). However, a causative relationship of apoptosis to the progenitor's defective clonogenic growth has not been sufficiently demonstrated. We investigated the degree of apoptosis and its contribution to ineffective hematopoiesis in MDS, by assessing the differential clonogenic capacity of purified "apoptotic" and "non-apoptotic" bone marrow progenitors in a short-term semisolid culture system. Although increased apoptosis was indeed detected in MDS bone marrow progenitors, there was no correlation between the existence of apoptosis and culture performance. Non-apoptotic as well as apoptotic CD34+ cells gave similar patterns of growth, both defective compared to normal. The ability of "apoptotic" CD34+ cells to proceed in colony formation as well as the abnormal growth of "non-apoptotic" progenitors are probably pointing towards the need to reconsider the role of apoptosis in the defective clonogenicity of MDS.


Assuntos
Apoptose , Células da Medula Óssea/patologia , Hematopoese , Síndromes Mielodisplásicas/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Anexina A5/metabolismo , Antígenos CD34/metabolismo , Células da Medula Óssea/metabolismo , Células Cultivadas , Feminino , Humanos , Técnicas In Vitro , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/metabolismo , Células-Tronco , Ensaio Tumoral de Célula-Tronco
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