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1.
Nature ; 506(7487): 240-4, 2014 Feb 13.
Artículo en Inglés | MEDLINE | ID: mdl-24429522

RESUMEN

Cells of the osteoblast lineage affect the homing and the number of long-term repopulating haematopoietic stem cells, haematopoietic stem cell mobilization and lineage determination and B cell lymphopoiesis. Osteoblasts were recently implicated in pre-leukaemic conditions in mice. However, a single genetic change in osteoblasts that can induce leukaemogenesis has not been shown. Here we show that an activating mutation of ß-catenin in mouse osteoblasts alters the differentiation potential of myeloid and lymphoid progenitors leading to development of acute myeloid leukaemia with common chromosomal aberrations and cell autonomous progression. Activated ß-catenin stimulates expression of the Notch ligand jagged 1 in osteoblasts. Subsequent activation of Notch signalling in haematopoietic stem cell progenitors induces the malignant changes. Genetic or pharmacological inhibition of Notch signalling ameliorates acute myeloid leukaemia and demonstrates the pathogenic role of the Notch pathway. In 38% of patients with myelodysplastic syndromes or acute myeloid leukaemia, increased ß-catenin signalling and nuclear accumulation was identified in osteoblasts and these patients showed increased Notch signalling in haematopoietic cells. These findings demonstrate that genetic alterations in osteoblasts can induce acute myeloid leukaemia, identify molecular signals leading to this transformation and suggest a potential novel pharmacotherapeutic approach to acute myeloid leukaemia.


Asunto(s)
Transformación Celular Neoplásica/genética , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patología , Mutación/genética , Osteoblastos/metabolismo , beta Catenina/genética , beta Catenina/metabolismo , Anemia/genética , Anemia/metabolismo , Anemia/patología , Animales , Secuencia de Bases , Proteínas de Unión al Calcio/deficiencia , Proteínas de Unión al Calcio/genética , Proteínas de Unión al Calcio/metabolismo , Diferenciación Celular/genética , Linaje de la Célula , Núcleo Celular/metabolismo , Transformación Celular Neoplásica/patología , Aberraciones Cromosómicas , Femenino , Células Madre Hematopoyéticas/metabolismo , Células Madre Hematopoyéticas/patología , Humanos , Péptidos y Proteínas de Señalización Intercelular/deficiencia , Péptidos y Proteínas de Señalización Intercelular/genética , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Proteína Jagged-1 , Leucemia Mieloide Aguda/metabolismo , Ligandos , Masculino , Proteínas de la Membrana/deficiencia , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Ratones , Síndromes Mielodisplásicos/genética , Síndromes Mielodisplásicos/metabolismo , Síndromes Mielodisplásicos/patología , Células Mieloides/metabolismo , Células Mieloides/patología , Osteoblastos/patología , Receptores Notch/metabolismo , Proteínas Serrate-Jagged , Transducción de Señal , Microambiente Tumoral/genética
2.
Blood ; 124(18): 2834-46, 2014 Oct 30.
Artículo en Inglés | MEDLINE | ID: mdl-25139351

RESUMEN

The bone marrow niche is thought to act as a permissive microenvironment required for emergence or progression of hematologic cancers. We hypothesized that osteoblasts, components of the niche involved in hematopoietic stem cell (HSC) function, influence the fate of leukemic blasts. We show that osteoblast numbers decrease by 55% in myelodysplasia and acute myeloid leukemia patients. Further, genetic depletion of osteoblasts in mouse models of acute leukemia increased circulating blasts and tumor engraftment in the marrow and spleen leading to higher tumor burden and shorter survival. Myelopoiesis increased and was coupled with a reduction in B lymphopoiesis and compromised erythropoiesis, suggesting that hematopoietic lineage/progression was altered. Treatment of mice with acute myeloid or lymphoblastic leukemia with a pharmacologic inhibitor of the synthesis of duodenal serotonin, a hormone suppressing osteoblast numbers, inhibited loss of osteoblasts. Maintenance of the osteoblast pool restored normal marrow function, reduced tumor burden, and prolonged survival. Leukemia prevention was attributable to maintenance of osteoblast numbers because inhibition of serotonin receptors alone in leukemic blasts did not affect leukemia progression. These results suggest that osteoblasts play a fundamental role in propagating leukemia in the marrow and may be a therapeutic target to induce hostility of the niche to leukemia blasts.


Asunto(s)
Progresión de la Enfermedad , Leucemia/patología , Osteoblastos/patología , Animales , Recuento de Células , Linaje de la Célula/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Hematopoyesis/efectos de los fármacos , Células Madre Hematopoyéticas/efectos de los fármacos , Células Madre Hematopoyéticas/patología , Humanos , Leucemia/tratamiento farmacológico , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/patología , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Osteoblastos/efectos de los fármacos , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/patología , Pirimidinas/farmacología , Pirimidinas/uso terapéutico
3.
Blood ; 121(16): 3246-53, 2013 Apr 18.
Artículo en Inglés | MEDLINE | ID: mdl-23422750

RESUMEN

Terminal erythroid differentiation starts from morphologically recognizable proerythroblasts that proliferate and differentiate to generate red cells. Although this process has been extensively studied in mice, its characterization in humans is limited. By examining the dynamic changes of expression of membrane proteins during in vitro human terminal erythroid differentiation, we identified band 3 and α4 integrin as optimal surface markers for isolating 5 morphologically distinct populations at successive developmental stages. Functional analysis revealed that these purified cell populations have distinct mitotic capacity. Use of band 3 and α4 integrin enabled us to isolate erythroblasts at specific developmental stages from primary human bone marrow. The ratio of erythroblasts at successive stages followed the predicted 1:2:4:8:16 pattern. In contrast, bone marrows from myelodysplastic syndrome patients exhibited altered terminal erythroid differentiation profiles. Thus, our findings not only provide new insights into the genesis of the red cell membrane during human terminal erythroid differentiation but also offer a means of isolating and quantifying each developmental stage during terminal erythropoiesis in vivo. Our findings should facilitate a comprehensive cellular and molecular characterization of each specific developmental stage of human erythroblasts and should provide a powerful means of identifying stage-specific defects in diseases associated with pathological erythropoiesis.


Asunto(s)
Eritroblastos/citología , Eritropoyesis , Proteína 1 de Intercambio de Anión de Eritrocito/análisis , Antígenos CD34/análisis , Células de la Médula Ósea/citología , Células de la Médula Ósea/patología , Separación Celular/métodos , Células Cultivadas , Proteínas del Citoesqueleto/análisis , Eritroblastos/patología , Citometría de Flujo/métodos , Humanos , Immunoblotting , Integrina alfa4/análisis , Proteínas de la Membrana/análisis , Mitosis , Síndromes Mielodisplásicos/patología
4.
N Engl J Med ; 364(26): 2496-506, 2011 Jun 30.
Artículo en Inglés | MEDLINE | ID: mdl-21714648

RESUMEN

BACKGROUND: Myelodysplastic syndromes are clinically heterogeneous disorders characterized by clonal hematopoiesis, impaired differentiation, peripheral-blood cytopenias, and a risk of progression to acute myeloid leukemia. Somatic mutations may influence the clinical phenotype but are not included in current prognostic scoring systems. METHODS: We used a combination of genomic approaches, including next-generation sequencing and mass spectrometry-based genotyping, to identify mutations in samples of bone marrow aspirate from 439 patients with myelodysplastic syndromes. We then examined whether the mutation status for each gene was associated with clinical variables, including specific cytopenias, the proportion of blasts, and overall survival. RESULTS: We identified somatic mutations in 18 genes, including two, ETV6 and GNAS, that have not been reported to be mutated in patients with myelodysplastic syndromes. A total of 51% of all patients had at least one point mutation, including 52% of the patients with normal cytogenetics. Mutations in RUNX1, TP53, and NRAS were most strongly associated with severe thrombocytopenia (P<0.001 for all comparisons) and an increased proportion of bone marrow blasts (P<0.006 for all comparisons). In a multivariable Cox regression model, the presence of mutations in five genes retained independent prognostic significance: TP53 (hazard ratio for death from any cause, 2.48; 95% confidence interval [CI], 1.60 to 3.84), EZH2 (hazard ratio, 2.13; 95% CI, 1.36 to 3.33), ETV6 (hazard ratio, 2.04; 95% CI, 1.08 to 3.86), RUNX1 (hazard ratio, 1.47; 95% CI, 1.01 to 2.15), and ASXL1 (hazard ratio, 1.38; 95% CI, 1.00 to 1.89). CONCLUSIONS: Somatic point mutations are common in myelodysplastic syndromes and are associated with specific clinical features. Mutations in TP53, EZH2, ETV6, RUNX1, and ASXL1 are predictors of poor overall survival in patients with myelodysplastic syndromes, independently of established risk factors. (Funded by the National Institutes of Health and others.).


Asunto(s)
Síndromes Mielodisplásicos/genética , Mutación Puntual , Células de la Médula Ósea , Análisis Citogenético , Análisis Mutacional de ADN , Genotipo , Humanos , Espectrometría de Masas , Persona de Mediana Edad , Síndromes Mielodisplásicos/mortalidad , Pronóstico , Modelos de Riesgos Proporcionales , Análisis de Secuencia de ADN , Análisis de Supervivencia
5.
Nature ; 451(7176): 335-9, 2008 Jan 17.
Artículo en Inglés | MEDLINE | ID: mdl-18202658

RESUMEN

Somatic chromosomal deletions in cancer are thought to indicate the location of tumour suppressor genes, by which a complete loss of gene function occurs through biallelic deletion, point mutation or epigenetic silencing, thus fulfilling Knudson's two-hit hypothesis. In many recurrent deletions, however, such biallelic inactivation has not been found. One prominent example is the 5q- syndrome, a subtype of myelodysplastic syndrome characterized by a defect in erythroid differentiation. Here we describe an RNA-mediated interference (RNAi)-based approach to discovery of the 5q- disease gene. We found that partial loss of function of the ribosomal subunit protein RPS14 phenocopies the disease in normal haematopoietic progenitor cells, and also that forced expression of RPS14 rescues the disease phenotype in patient-derived bone marrow cells. In addition, we identified a block in the processing of pre-ribosomal RNA in RPS14-deficient cells that is functionally equivalent to the defect in Diamond-Blackfan anaemia, linking the molecular pathophysiology of the 5q- syndrome to a congenital syndrome causing bone marrow failure. These results indicate that the 5q- syndrome is caused by a defect in ribosomal protein function and suggest that RNAi screening is an effective strategy for identifying causal haploinsufficiency disease genes.


Asunto(s)
Cromosomas Humanos Par 5/genética , Ligamiento Genético/genética , Predisposición Genética a la Enfermedad/genética , Interferencia de ARN , Proteínas Ribosómicas/genética , Anemia de Diamond-Blackfan/genética , Anemia de Diamond-Blackfan/fisiopatología , Diferenciación Celular , Células Cultivadas , Deleción Cromosómica , Células Eritroides/citología , Células Eritroides/metabolismo , Células Madre Hematopoyéticas/metabolismo , Humanos , Fenotipo , Precursores del ARN/genética , Precursores del ARN/metabolismo , ARN Ribosómico/genética , ARN Ribosómico/metabolismo , ARN Ribosómico 18S/genética , Proteínas Ribosómicas/deficiencia , Proteínas Ribosómicas/metabolismo , Ribosomas/química , Ribosomas/genética , Ribosomas/metabolismo , Síndrome
6.
Blood ; 118(17): 4666-73, 2011 Oct 27.
Artículo en Inglés | MEDLINE | ID: mdl-21873545

RESUMEN

Large chromosomal deletions are among the most common molecular abnormalities in cancer, yet the identification of relevant genes has proven difficult. The 5q- syndrome, a subtype of myelodysplastic syndrome (MDS), is a chromosomal deletion syndrome characterized by anemia and thrombocytosis. Although we have previously shown that hemizygous loss of RPS14 recapitulates the failed erythroid differentiation seen in 5q- syndrome, it does not affect thrombocytosis. Here we show that a microRNA located in the common deletion region of 5q- syndrome, miR-145, affects megakaryocyte and erythroid differentiation. We find that miR-145 functions through repression of Fli-1, a megakaryocyte and erythroid regulatory transcription factor. Patients with del(5q) MDS have decreased expression of miR-145 and increased expression of Fli-1. Overexpression of miR-145 or inhibition of Fli-1 decreases the production of megakaryocytic cells relative to erythroid cells, whereas inhibition of miR-145 or overexpression of Fli-1 has a reciprocal effect. Moreover, combined loss of miR-145 and RPS14 cooperates to alter erythroid-megakaryocytic differentiation in a manner similar to the 5q- syndrome. Taken together, these findings demonstrate that coordinate deletion of a miRNA and a protein-coding gene contributes to the phenotype of a human malignancy, the 5q- syndrome.


Asunto(s)
Anemia Macrocítica/genética , MicroARNs/genética , Sistemas de Lectura Abierta/genética , Anemia Macrocítica/etiología , Animales , Estudios de Casos y Controles , Diferenciación Celular/genética , Deleción Cromosómica , Cromosomas Humanos Par 5/genética , Células Eritroides/metabolismo , Eritropoyesis/genética , Eritropoyesis/fisiología , Humanos , Pérdida de Heterocigocidad , Megacariocitos/metabolismo , Megacariocitos/fisiología , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , MicroARNs/metabolismo , MicroARNs/fisiología , Síndromes Mielodisplásicos/genética , Síndromes Mielodisplásicos/patología , Proteína Proto-Oncogénica c-fli-1/genética , Proteína Proto-Oncogénica c-fli-1/metabolismo , Proteína Proto-Oncogénica c-fli-1/fisiología , Proteínas Ribosómicas/genética , Proteínas Ribosómicas/metabolismo , Proteínas Ribosómicas/fisiología , Células Tumorales Cultivadas
7.
Cancer ; 118(8): 2138-47, 2012 Apr 15.
Artículo en Inglés | MEDLINE | ID: mdl-21887679

RESUMEN

BACKGROUND: Ezatiostat is a glutathione analog prodrug glutathione S-transferase P1-1 (GSTP1-1) inhibitor. This study evaluated 2 extended dose schedules of oral ezatiostat in 89 heavily pretreated patients with low to intermediate-1 risk myelodysplastic syndrome (MDS). METHODS: Patients were randomized by 1 stratification factor-baseline cytopenia (anemia only vs anemia with additional cytopenias)-to 1 of 2 extended dosing schedules. Multilineage hematologic improvement (HI) responses were assessed by International Working Group 2006 criteria. RESULTS: Overall, 11 of 38 (29%) red blood cell (RBC) transfusion-dependent patients had HI-Erythroid (HI-E) response. The median duration of HI-E response was 34 weeks. Multilineage responses were observed. There was 1 cytogenetic complete response in a del (5q) MDS patient. An important trend was the effect of prior therapy on response. A 40% HI-E rate (6 of 15 patients) was observed in patients who had prior lenalidomide and no prior hypomethylating agents (HMAs), with 5 of 11 (45%) patients achieving significant RBC transfusion reduction and 3 of 11 (27%) achieving transfusion independence. A 28% HI-E rate (5 of 18 patients) was observed in patients who were both lenalidomide and HMA naive, with 4 of 8 (50%) patients achieving clinically significant RBC transfusion reductions. Most common ezatiostat-related adverse events were grade 1 and 2 gastrointestinal including: nausea (45%, 17%), diarrhea (26%, 7%), and vomiting (30%, 12%). CONCLUSIONS: Ezatiostat is the first GSTP1-1 inhibitor shown to cause clinically significant and sustained reduction in RBC transfusions, transfusion independence, and multilineage responses in MDS patients. The tolerability and activity profile of ezatiostat may offer a new treatment option for patients with MDS.


Asunto(s)
Antineoplásicos/administración & dosificación , Glutatión/análogos & derivados , Administración Oral , Anciano , Anciano de 80 o más Años , Antineoplásicos/efectos adversos , Esquema de Medicación , Femenino , Glutatión/administración & dosificación , Glutatión/efectos adversos , Humanos , Masculino , Persona de Mediana Edad , Síndromes Mielodisplásicos/tratamiento farmacológico , Factores de Riesgo
8.
Cancer Causes Control ; 22(4): 623-9, 2011 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-21287258

RESUMEN

Myelodysplastic syndromes (MDS) are a group of hematological malignancies with poor survival. Although previous studies have identified the prognostic role of multiple demographic and clinical characteristics, the potential role of lifestyle factors has not been evaluated. In this study, we conducted an extensive assessment of the predictors of MDS survival, with a special focus on lifestyle factors. A total of 616 patients (median survival = 4.1 years) were included in the analysis, and multivariate Cox proportional hazard models were utilized to estimate hazard ratios. Compared with non-smokers, MDS patients who smoked at the initial clinical encounter had a significantly increased risk of death [hazard ratio (HR) = 1.46, 95% confidence intervals (CI): 1.07-2.00]. The elevated risk was restricted to men (HR = 1.76, 95% CI: 1.21-2.56) and not observed among women (HR = 0.98, 95% CI: 0.51-1.85). When patients were stratified by the IPSS categorization, a near three fold increased risk of death was associated with smoking among patients with low-risk MDS (HR = 2.83, 95% CI: 1.48-5.39), whereas smoking did not appear to influence the survival of patients with intermediate- or high-risk MDS. This study was the first to identify smoking as a significant and independent predictor of MDS survival, particularly among low-risk patients.


Asunto(s)
Síndromes Mielodisplásicos/mortalidad , Fumar/efectos adversos , Fumar/epidemiología , Anciano , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Síndromes Mielodisplásicos/complicaciones , Síndromes Mielodisplásicos/diagnóstico , Síndromes Mielodisplásicos/epidemiología , Pronóstico , Factores de Riesgo , Caracteres Sexuales , Fumar/mortalidad , Análisis de Supervivencia , Factores de Tiempo
9.
Blood ; 113(26): 6533-40, 2009 Jun 25.
Artículo en Inglés | MEDLINE | ID: mdl-19398716

RESUMEN

Phase 1 testing of ezatiostat, a glutathione S-transferase P1-1 inhibitor, for the treatment of myelodysplastic syndrome was conducted in a multidose-escalation study. Patients received 10 dose levels (200, 400, 1000, 1400, 2000, 2400, 3000, 4000, 5000, and 6000 mg) of ezatiostat tablets in divided doses on days 1 to 7 of a 21-day cycle for a maximum of 8 cycles. The safety and pharmacokinetics of ezatiostat were evaluated. Forty-five patients with low to intermediate-2 International Prognostic Scoring System risk myelodysplastic syndrome were enrolled. No dose-limiting toxicities were observed. The most common grade 1 or 2, respectively, treatment-related adverse events were nonhematologic: nausea (56%, 9%), diarrhea (36%, 7%), vomiting (24%, 7%), abdominal pain (9%, 0%), constipation (4%, 9%), anorexia (3%, 7%), and dyspepsia (3%, 7%). Concentration of the primary active metabolite, TLK236, increased proportionate to ezatiostat dosage. Seventeen hematologic improvement (HI) responses by International Working Group criteria were observed at dose levels of 200 to 6000 mg/day with 11 HI responses at doses of 4000 to 6000 mg/day. HI responses occurred in all lineages including 3 bilineage and 1 complete cytogenetic response. Decreased number of red blood cell and platelet transfusions and in some cases transfusion independence were attained. Extended dose schedules of ezatiostat tablets are under investigation.


Asunto(s)
Glutatión/análogos & derivados , Síndromes Mielodisplásicos/tratamiento farmacológico , Profármacos/uso terapéutico , Dolor Abdominal/inducido químicamente , Anciano , Anciano de 80 o más Años , Biotransformación , Relación Dosis-Respuesta a Droga , Femenino , Fiebre/inducido químicamente , Interacciones Alimento-Droga , Enfermedades Gastrointestinales/inducido químicamente , Glutatión/administración & dosificación , Glutatión/efectos adversos , Glutatión/farmacocinética , Glutatión/uso terapéutico , Humanos , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Neutropenia/inducido químicamente , Profármacos/administración & dosificación , Profármacos/efectos adversos , Profármacos/farmacocinética , Comprimidos
10.
Cancer Res ; 67(3): 992-1000, 2007 Feb 01.
Artículo en Inglés | MEDLINE | ID: mdl-17283131

RESUMEN

The tumor suppressor gene INK4b (p15) is silenced by CpG island hypermethylation in most acute myelogenous leukemias (AML), and this epigenetic phenomenon can be reversed by treatment with hypomethylating agents. Thus far, it was not investigated whether INK4b is hypermethylated in all cytogenetic subtypes of AML. A comparison of levels of INK4b methylation in AML with the three most common cytogenetic alterations, inv(16), t(8;21), and t(15;17), revealed a strikingly low level of methylation in all leukemias with inv(16) compared with the other types. Surprisingly, the expression level of INK4b in inv(16)+ AML samples was low and comparable with that of the other subtypes. An investigation into an alternative mechanism of INK4b silencing determined that the loss of INK4b expression was caused by inv(16)-encoded core binding factor beta-smooth muscle myosin heavy chain (CBFbeta-SMMHC). The silencing was manifested in an inability to activate the normal expression of INK4b RNA as shown in vitamin D3-treated U937 cells expressing CBFbeta-SMMHC. CBFbeta-SMMHC was shown to displace RUNX1 from a newly determined CBF site in the promoter of INK4b. Importantly, this study (a) establishes that the gene encoding the tumor suppressor p15(INK4b) is a target of CBFbeta-SMMHC, a finding relevant to the leukemogenesis process, and (b) indicates that, in patients with inv(16)-containing AML, reexpression from the INK4b locus in the leukemia would not be predicted to occur using hypomethylating drugs.


Asunto(s)
Inversión Cromosómica , Cromosomas Humanos Par 6 , Subunidad beta del Factor de Unión al Sitio Principal/genética , Inhibidor p15 de las Quinasas Dependientes de la Ciclina/antagonistas & inhibidores , Inhibidor p15 de las Quinasas Dependientes de la Ciclina/genética , Leucemia Mieloide Aguda/genética , Cadenas Pesadas de Miosina/genética , Subunidad alfa 2 del Factor de Unión al Sitio Principal/metabolismo , Inhibidor p15 de las Quinasas Dependientes de la Ciclina/biosíntesis , Metilación de ADN , Silenciador del Gen , Humanos , Regiones Promotoras Genéticas , ARN Neoplásico/biosíntesis , ARN Neoplásico/genética , Activación Transcripcional
11.
PLoS Med ; 5(2): e35, 2008 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-18271621

RESUMEN

BACKGROUND: Lenalidomide is an effective new agent for the treatment of patients with myelodysplastic syndrome (MDS), an acquired hematopoietic disorder characterized by ineffective blood cell production and a predisposition to the development of leukemia. Patients with an interstitial deletion of Chromosome 5q have a high rate of response to lenalidomide, but most MDS patients lack this deletion. Approximately 25% of patients without 5q deletions also benefit from lenalidomide therapy, but response in these patients cannot be predicted by any currently available diagnostic assays. The aim of this study was to develop a method to predict lenalidomide response in order to avoid unnecessary toxicity in patients unlikely to benefit from treatment. METHODS AND FINDINGS: Using gene expression profiling, we identified a molecular signature that predicts lenalidomide response. The signature was defined in a set of 16 pretreatment bone marrow aspirates from MDS patients without 5q deletions, and validated in an independent set of 26 samples. The response signature consisted of a cohesive set of erythroid-specific genes with decreased expression in responders, suggesting that a defect in erythroid differentiation underlies lenalidomide response. Consistent with this observation, treatment with lenalidomide promoted erythroid differentiation of primary hematopoietic progenitor cells grown in vitro. CONCLUSIONS: These studies indicate that lenalidomide-responsive patients have a defect in erythroid differentiation, and suggest a strategy for a clinical test to predict patients most likely to respond to the drug. The experiments further suggest that the efficacy of lenalidomide, whose mechanism of action in MDS is unknown, may be due to its ability to induce erythroid differentiation.


Asunto(s)
Diferenciación Celular/genética , Células Precursoras Eritroides/fisiología , Eritropoyesis/genética , Síndromes Mielodisplásicos/tratamiento farmacológico , Síndromes Mielodisplásicos/genética , Talidomida/análogos & derivados , Adulto , Anciano , Anciano de 80 o más Años , Diferenciación Celular/efectos de los fármacos , Células Cultivadas , Deleción Cromosómica , Cromosomas Humanos Par 5/efectos de los fármacos , Cromosomas Humanos Par 5/genética , Ensayos Clínicos Fase II como Asunto/métodos , Células Precursoras Eritroides/efectos de los fármacos , Eritropoyesis/efectos de los fármacos , Perfilación de la Expresión Génica/métodos , Marcadores Genéticos/efectos de los fármacos , Marcadores Genéticos/genética , Células Madre Hematopoyéticas/efectos de los fármacos , Células Madre Hematopoyéticas/fisiología , Humanos , Lenalidomida , Masculino , Persona de Mediana Edad , Síndromes Mielodisplásicos/sangre , Valor Predictivo de las Pruebas , Talidomida/farmacología , Talidomida/uso terapéutico
12.
Leuk Res ; 32(4): 553-8, 2008 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-17888511

RESUMEN

Hypocellular myelodysplastic syndrome (MDS) represents only a small portion of MDS, of which, the clinical significance has not been well-defined. By using currently accepted age-adjusted criteria to define hypocellularity as <30% in patients <70 years old, and <20% in >70 years old, we identified 163 (15.5%) hypocelluar MDS from 1049 consecutive adult MDS patients over an 11-year period (1995-2006). Compared to normal/hypercellular MDS, hypocellular MDS patients were younger (p<0.01), less anemic (p=0.02), but more neutropenic (p<0.001) and thrombocytopenic (p=0.05), and had a comparable cytogenetic risk group distribution (p=0.09) and international prognostic scores (IPSS, p=0.13). With a median follow-up of 52 months, hypocellular MDS showed a favorable overall survival (56 months versus 28 months, log-rank p<0.0001) over normal/hypocellular MDS, and this survival preference was also demonstrated in all IPSS groups and cytogenetic risk groups, and was independent of all other risk factors (Cox regression test, p=0.01). In conclusion, our study demonstrated that hypocellular MDS has characteristic clinicopathologic features, and bone marrow hypocellularity in MDS is an independent factor which predicts a favorable outcome.


Asunto(s)
Médula Ósea/patología , Síndromes Mielodisplásicos/patología , Adulto , Distribución por Edad , Anciano , Anciano de 80 o más Años , Femenino , Estudios de Seguimiento , Humanos , Técnicas para Inmunoenzimas , Incidencia , Cariotipificación , Masculino , Persona de Mediana Edad , Síndromes Mielodisplásicos/mortalidad , Pronóstico , Tasa de Supervivencia
14.
Blood Adv ; 2(12): 1393-1402, 2018 06 26.
Artículo en Inglés | MEDLINE | ID: mdl-29903708

RESUMEN

Anemia is the defining feature in most patients with myelodysplastic syndromes (MDS), yet defects in erythropoiesis have not been well characterized. We examined freshly obtained bone marrow (BM) samples for stage-specific abnormalities during terminal erythroid differentiation (TED) from 221 samples (MDS, n = 205 from 113 unique patients; normal, n = 16) by measuring the surface expression of glycophorin A, band 3, and integrin α-4. Clinical and biologic associations were sought with presence or absence of TED and the specific stage of erythroid arrest. In 27% of MDS samples (56/205), there was no quantifiable TED documented by surface expression of integrin α-4 and band 3 by terminally differentiating erythroblasts. Absence of quantifiable TED was associated with a significantly worse overall survival (56 vs 103 months, P = .0001) and SRSF2 mutations (7/23, P < .05). In a multivariable Cox proportional hazards regression analysis, absence of TED remained independently significant across International Prognostic Scoring System-Revised (IPSS-R) categories, myeloid/erythroid ratio, and mutations in several genes. In 149/205 MDS samples, the proportion of cells undergoing TED did not follow the expected 1:2:4:8:16 doubling pattern in successive stages. Absence of TED emerged as a powerful independent prognostic marker of poor overall survival across all IPSS-R categories in MDS, and SRSF2 mutations were more frequently associated with absence of TED.


Asunto(s)
Diferenciación Celular , Eritrocitos/citología , Síndromes Mielodisplásicos/diagnóstico , Médula Ósea/metabolismo , Médula Ósea/patología , Eritropoyesis , Humanos , Mutación , Síndromes Mielodisplásicos/mortalidad , Síndromes Mielodisplásicos/patología , Pronóstico , Factores de Empalme Serina-Arginina/genética , Análisis de Supervivencia
15.
Leuk Res ; 31(1): 19-26, 2007 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-17064768

RESUMEN

The myelodysplastic syndromes (MDS) are a collection of hematopoietic disorders with varying degrees of mono- to trilineage cytopenias and bone marrow dysplasia. In recent years much progress has been made in the treatment of MDS and there are now several therapeutic compounds used with varying levels of success. These compounds typically cause side effects that make them unattractive for treatment of patients in the early stages of MDS. Naturally occurring compounds that are not toxic may provide a means to treat patients in the initial stages of disease. We conducted a pilot study to test the efficacy of coenzyme Q10 (coQ10) in MDS patients with low to intermediate-2 risk disease. A variety of responses were observed in 7 of 29 patients including two trilineage and two cytogenetic responses. Sequencing mitochondrial DNA (mtDNA) from pretreatment bone marrows showed multiple mutations, some resulting in amino acid changes, in 3/5 nonresponders, 1/4 responders and in two control samples. We conclude that coQ10 may be of clinical benefit in a subset of MDS patients, but responders cannot be easily pre-selected on the basis of either the conventional clinical and pathologic characteristics or mtDNA mutations.


Asunto(s)
Síndromes Mielodisplásicos/tratamiento farmacológico , Trombocitopenia/prevención & control , Ubiquinona/análogos & derivados , Anciano , Anciano de 80 o más Años , Secuencia de Bases , Células de la Médula Ósea/química , Células de la Médula Ósea/patología , Coenzimas , ADN Mitocondrial/genética , ADN Mitocondrial/aislamiento & purificación , Femenino , Humanos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Leucocitos Mononucleares/química , Leucocitos Mononucleares/patología , Masculino , Persona de Mediana Edad , Mutación , Síndromes Mielodisplásicos/genética , Síndromes Mielodisplásicos/fisiopatología , Trombocitopenia/etiología , Trombocitopenia/genética , Ubiquinona/uso terapéutico
16.
Am J Clin Pathol ; 126(5): 789-97, 2006 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-17050076

RESUMEN

The majority of chronic myelomonocytic leukemia (CMML) cases arise de novo; cases evolving from preexisting myelodysplasia (MDS) or myeloproliferative diseases have not been well-studied. We conducted the present study to determine the clinicopathologic features and to study possible underlying molecular and cytogenetic mechanisms involved in this evolution. Between April 1995 and November 2005, we identified 120 CMML cases, of which 20 (16.7%) had a previous diagnosis of MDS. Of the 20 patients with MDS, 6 had relative monocytosis at diagnosis. At the time of MDS to CMML evolution, mutations in JAK2 (V617F), FLT3 (ITD), K-ras-2, or N-ras were not acquired, and only 1 (6%) of 17 evaluable cases showed cytogenetic progression. The median time to evolution from MDS to CMML was 29 months, and the median survival following CMML development was 13 months. Three cases (17%) transformed to acute myeloid leukemia. These findings indicate that in some cases of otherwise typical MDS, the progenitor cells may have some capacity for monocytic proliferation at diagnosis and manifest rapid disease progression once a monocytic proliferation supervenes.


Asunto(s)
Leucemia Mielomonocítica Crónica/patología , Trastornos Mieloproliferativos/complicaciones , Defectos del Tubo Neural/complicaciones , Anciano , Anciano de 80 o más Años , ADN/química , ADN/genética , Análisis Mutacional de ADN , Humanos , Janus Quinasa 2/genética , Estimación de Kaplan-Meier , Cariotipificación , Leucemia Mielomonocítica Crónica/etiología , Leucemia Mielomonocítica Crónica/genética , Masculino , Persona de Mediana Edad , Mutación/genética , Tirosina Quinasa 3 Similar a fms/genética , Proteínas ras/genética
17.
Leuk Lymphoma ; 47(3): 433-40, 2006 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-16396766

RESUMEN

This phase II trial investigated the safety and preliminary efficacy of a topotecan/thalidomide combination therapy in patients with myelodysplastic syndrome who had refractory anemia with excess blasts (RAEB), RAEB with transformation, or chronic myelomonocytic anemia. Patients received three 21-day cycles of topotecan 1.25 mg/m(2) on days 1-5, which was repeated for two additional cycles in patients whose bone marrow blast percentages did not decrease. Oral thalidomide was then started at 100 mg/day (with the dose escalated up to 300 mg/day if well tolerated) for up to 1 year. Patients were monitored throughout the trial for hematologic and clinical adverse events, and efficacy was assessed using International Working Group (IWG) criteria. Forty-five patients, mostly elderly (median age 68 years; range 52-79 years), were enrolled. Therapy was generally well tolerated compared to high-dose chemotherapy. Three patients died from disease progression/infections during topotecan therapy, and four patients discontinued topotecan because of high-grade neutropenia (two patients), syncope (one patient), or hip surgery (one patient). Of 24 patients who received thalidomide, three discontinued because of treatment-related toxicity. Thirty-eight patients were evaluable for response: nine (24%) had hematologic improvement and 13 (34%) had stable disease. Responses occurred in patients with all disease subtypes. Six patients achieved transfusion independence, and one patient had a trilineage response. Approximately one-third of the patients had decreases in bone marrow blasts of 50%. Therefore, a topotecan and thalidomide combination therapy is promising, although further studies are needed to determine the optimum doses and schedule.


Asunto(s)
Síndromes Mielodisplásicos/tratamiento farmacológico , Talidomida/uso terapéutico , Topotecan/uso terapéutico , Anciano , Anemia Refractaria con Exceso de Blastos/tratamiento farmacológico , Anemia Refractaria con Exceso de Blastos/patología , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Quimioterapia Combinada , Tolerancia a Medicamentos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Síndromes Mielodisplásicos/patología , Factores de Riesgo , Talidomida/administración & dosificación , Talidomida/efectos adversos , Factores de Tiempo , Topotecan/administración & dosificación , Topotecan/efectos adversos , Resultado del Tratamiento
18.
Semin Hematol ; 41(2 Suppl 4): 13-20, 2004 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-15190511

RESUMEN

The myelodysplastic syndromes (MDS) continue to pose conceptual and practical conundrums because of their heterogeneity and therapeutic challenges. They are not restricted to the presence of clonal cells that are prone to excessive proliferation and premature apoptosis. In MDS the bone marrow microenvironment also is abnormal and exhibits an excess of proinflammatory cytokines, especially tumor necrosis factor (TNF), neoangiogenesis, and poorly defined immune defects. Thalidomide, a drug with anti-TNF, antiangiogenic, and immunomodulatory activities, and other agents with anti-TNF effects, such as pentoxifylline, etanercept, and infliximab, have produced hematologic improvement in 20% to 40% of patients. These agents may provide effective therapy for a subset of lower-risk MDS patients, even if the drugs target the bone marrow microenvironment predominantly. However, in higher-risk MDS patients, especially those with more than 10% blasts, it is important to eliminate abnormal cell clones; drugs used for this purpose have included arsenic trioxide, topotecan, the farnesyl transferase inhibitor tipifarnib, and demethylating agents, such as 5-azacytidine and decitabine. To increase the therapeutic index, a combination strategy may be preferable for higher-risk MDS patients, in whom the seed (clone) and the soil (bone marrow microenvironment) must be targeted simultaneously. The challenge is to recognize the subset that is likely to respond to a given drug so that patients can be preselected for therapy.


Asunto(s)
Síndromes Mielodisplásicos/tratamiento farmacológico , Animales , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Médula Ósea/efectos de los fármacos , Médula Ósea/patología , Células Clonales/efectos de los fármacos , Células Clonales/patología , Sistemas de Liberación de Medicamentos , Humanos , Síndromes Mielodisplásicos/mortalidad
19.
Leuk Res ; 27(6): 529-37, 2003 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-12648513

RESUMEN

A novel method for simultaneously detecting clonality by FISH, and presence of telomerase activity (telo+ cells) or histone H3 mRNA (H3+) in single cells from a mixed leukemic population is reported. The methods were validated using K562 cells mixed with peripheral blood granulocytes and bone marrow aspirate cells from newly diagnosed AML patients. Fifty patients with AML were analyzed for telo+ cells, while eight AML patients were analyzed for FISH-Telomerase and FISH-H3+ during remission induction therapy. Our results demonstrate that: (1). changes in the leukemic populations during therapy could be followed; (2). a favorable response to chemotherapy occurred when there was a reduction in both the cytogenetically abnormal cells along with reduction in telo+ cells within this abnormal population; (3). reduction of either telo+ cells or FISH+ cells alone did not correlate with good response. H3+ could be detected in only 4% of the leukemic population, most of which were cytogenetically abnormal. These newly established methods allow sub-populations of cells to be followed during disease progression and treatment and to elucidate factors that give a specific clone proliferative advantage.


Asunto(s)
Histonas/genética , Células K562/enzimología , Telomerasa/análisis , Enfermedad Aguda , Médula Ósea/enzimología , Médula Ósea/metabolismo , Cartilla de ADN/química , Granulocitos/enzimología , Granulocitos/metabolismo , Histonas/metabolismo , Humanos , Hibridación Fluorescente in Situ/métodos , Cariotipificación , Reacción en Cadena de la Polimerasa , Pronóstico , ARN Mensajero/análisis , Inducción de Remisión
20.
Leuk Res ; 28(8): 791-803, 2004 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-15203277

RESUMEN

Twenty-eight myelodysplastic syndromes (MDS) patients were treated with arsenic trioxide (ATO) and thalidomide. Seven patients responded including one complete hematologic and cytogenetic response and one with regression in spleen size. Two trilineage responses were seen in patients with inv(3)(q21q26.2). Three of five patients who had high pre-therapy EVI1 levels showed unexpectedly good responses while two died early in the first cycle. In vitro studies using 32Dcl3 cells forced to express EVI1 confirmed increased sensitivity of these cells to ATO. Both low/high risk MDS may benefit significantly from therapy with ATO/thalidomide, and those with high pre-therapy EVI1 expression may be uniquely sensitive.


Asunto(s)
Antineoplásicos/uso terapéutico , Arsenicales/uso terapéutico , Proteínas de Unión al ADN/metabolismo , Resistencia a Antineoplásicos , Síndromes Mielodisplásicos/tratamiento farmacológico , Óxidos/uso terapéutico , Proto-Oncogenes , Talidomida/uso terapéutico , Factores de Transcripción , Anciano , Trióxido de Arsénico , Linaje de la Célula , Proteínas de Unión al ADN/genética , Quimioterapia Combinada , Femenino , Humanos , Inmunosupresores/uso terapéutico , Proteína del Locus del Complejo MDS1 y EV11 , Masculino , Persona de Mediana Edad , Síndromes Mielodisplásicos/patología , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Factores de Riesgo , Bazo/metabolismo , Bazo/patología , Dedos de Zinc
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