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1.
Acta Haematol ; 146(6): 530-537, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37557081

RESUMEN

Chronic myelogenous leukemia at blast crisis with a T-cell phenotype (T-ALL CML-BC) at diagnosis, without any prior history of CML is extremely rare. After the introduction of tyrosine kinase inhibitors (TKIs), CML patients have a median survival comparable to general population and accelerated/blast crisis are rarely encountered. Most CML patients (80%) transform into acute myeloid leukemia and the rest into B-ALL. Anecdotal cases of Ph+ T-ALL, either de novo or in the context of CML-BC have been reported. Left shift in the blood, the presence of splenomegaly/extramedullary infiltration and the occurrence of BCR::ABL1 rearrangement in both the blastic population, as well as in the myeloid cell compartment are key points in differentiating de novo Ph+ T-ALL from T-ALL CML-BC. The latter is a rare entity, characterized by extramedullary disease, p210 transcript and clonal evolution. Lack of preceding CML does not rule out the diagnosis of T-ALL CML-BC. Prompt TKI treatment with ALL-directed therapy followed by allogeneic stem cell transplantation may offer long-term survival in this otherwise poor prognosis entity. In this paper, we describe a patient with T-ALL CML-BC at presentation, still alive 51 months after diagnosis and we offer a review of the literature on this rare subject. All clinical and laboratory features are provided in order to distinguish de novo Ph+ T-ALL from T-ALL CML-BC, underscoring the prognostic and therapeutic significance of such a differentiation.


Asunto(s)
Leucemia Mielógena Crónica BCR-ABL Positiva , Leucemia-Linfoma Linfoblástico de Células T Precursoras , Humanos , Crisis Blástica/terapia , Crisis Blástica/genética , Leucemia Mielógena Crónica BCR-ABL Positiva/diagnóstico , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Leucemia Mielógena Crónica BCR-ABL Positiva/terapia , Fenotipo , Leucemia-Linfoma Linfoblástico de Células T Precursoras/diagnóstico , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células T Precursoras/terapia , Linfocitos T
2.
Blood ; 119(5): 1208-13, 2012 Feb 02.
Artículo en Inglés | MEDLINE | ID: mdl-22053108

RESUMEN

The polycomb repressive complex 2 (PRC2) is a highly conserved histone H3 lysine 27 methyltransferase that regulates the expression of developmental genes. Inactivating mutations of the catalytic component of PRC2, EZH2, are seen in myeloid disorders. We reasoned that the other 2 core PRC2 components, SUZ12 and EED, may also be mutational targets in these diseases, as well as associated factors such as JARID2. SUZ12 mutations were identified in 1 of 2 patients with myelodysplastic syndrome/myeloproliferative neoplasms with 17q acquired uniparental disomy and in 2 of 2 myelofibrosis cases with focal 17q11 deletions. All 3 were missense mutations affecting the highly conserved VEFS domain. Analysis of a further 146 myelodysplastic syndrome/myeloproliferative neoplasm patients revealed an additional VEFS domain mutant, yielding a total mutation frequency of 1.4% (2 of 148). We did not find mutations of JARID2 or EED in association with acquired uniparental disomy for chromosome 6p or 11q, respectively; however, screening unselected cases identified missense mutations in EED (1 of 148; 1%) and JARID2 (3 of 148; 2%). All 3 SUZ12 mutations tested and the EED mutation reduced PRC2 histone methyltransferase activity in vitro, demonstrating that PRC2 function may be compromised in myeloid disorders by mutation of distinct genes.


Asunto(s)
Neoplasias de la Médula Ósea/genética , Silenciador del Gen , Enfermedades Mielodisplásicas-Mieloproliferativas/genética , Trastornos Mieloproliferativos/genética , Proteínas Represoras/genética , Anciano , Anciano de 80 o más Años , Secuencia de Aminoácidos , Estudios de Cohortes , Análisis Mutacional de ADN , Femenino , Silenciador del Gen/fisiología , Humanos , Masculino , Persona de Mediana Edad , Datos de Secuencia Molecular , Proteínas del Grupo Polycomb , Homología de Secuencia de Aminoácido
3.
Blood ; 118(19): 5227-34, 2011 Nov 10.
Artículo en Inglés | MEDLINE | ID: mdl-21921040

RESUMEN

We genotyped 370 subjects with primary myelofibrosis (PMF) and 148 with postpolycythemia vera/postessential thrombocythemia (PPV/PET) MF for mutations of EZH2. Mutational status at diagnosis was correlated with hematologic parameters, clinical manifestations, and outcome. A total of 25 different EZH2 mutations were detected in 5.9% of PMF, 1.2% of PPV-MF, and 9.4% of PET-MF patients; most were exonic heterozygous missense changes. EZH2 mutation coexisted with JAK2V617F or ASXL1 mutation in 12 of 29 (41.4%) and 6 of 27 (22.2%) evaluated patients; TET2 and CBL mutations were found in 2 and 1 patients, respectively. EZH2-mutated PMF patients had significantly higher leukocyte counts, blast-cell counts, and larger spleens at diagnosis, and most of them (52.6%) were in the high-risk International Prognostic Score System (IPSS) category. After a median follow-up of 39 months, 128 patients (25.9%) died, 81 (63.3%) because of leukemia. Leukemia-free survival (LFS) and overall survival (OS) were significantly reduced in EZH2-mutated PMF patients (P = .028 and P < .001, respectively); no such impact was seen for PPV/PET-MF patients, possibly due to the low number of mutated cases. In multivariate analysis, survival of PMF patients was predicted by IPSS high-risk category, a < 25% JAK2V617F allele burden, and EZH2 mutation status. We conclude that EZH2 mutations are independently associated with shorter survival in patients with PMF.


Asunto(s)
Proteínas de Unión al ADN/genética , Mutación , Mielofibrosis Primaria/genética , Factores de Transcripción/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Supervivencia sin Enfermedad , Proteína Potenciadora del Homólogo Zeste 2 , Exones , Femenino , Heterocigoto , Humanos , Janus Quinasa 2/genética , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Mutación Missense , Complejo Represivo Polycomb 2 , Policitemia Vera/etiología , Policitemia Vera/genética , Mielofibrosis Primaria/complicaciones , Pronóstico , Proteínas Represoras/genética , Trombocitemia Esencial/etiología , Trombocitemia Esencial/genética , Adulto Joven
4.
Infect Dis (Lond) ; 55(10): 706-715, 2023 10.
Artículo en Inglés | MEDLINE | ID: mdl-37427461

RESUMEN

BACKGROUND: Omicron-1 COVID-19 is less invasive in the general population than previous viral variants. However, clinical course and outcome of hospitalised patients with SARS-CoV-2 pneumonia during the shift of the predominance from Delta to Omicron variants are not fully explored. METHODS: During January 2022 consecutively hospitalised patients with SARS-CoV-2 pneumonia were analysed. SARS-CoV-2 variants were identified by a 2-step pre-screening protocol and randomly confirmed by whole genome sequencing analysis. Clinical, laboratory and treatment data split by type of variant were analysed along with logistic regression of factors associated to mortality. RESULTS: 150 patients [mean age (SD) 67.2(15.8) years, male 54%] were analysed. Compared to Delta (n = 46), Omicron-1 patients (n = 104) were older [mean age (SD): 69.5(15.4) vs 61.9(15.8) years, p = 0.007], with more comorbidities (89.4% vs 65.2%, p = 0.001), less obesity (BMI >30Kg/m2 in 24% vs 43.5%, p = 0.034) but higher vaccination rates for COVID-19 (52.9% vs 8.7%, p < 0.001). Severe pneumonia (48.7%), pulmonary embolism (4.7%), need for invasive mechanical ventilation (8%), administration of dexamethasone (76%) and 60-day mortality (22.6%) did not significantly differ. Severe SARS-CoV-2 pneumonia independently predicted mortality [OR 8.297 (CI95% 2.080-33.095), p = 0.003]. Remdesivir administration (n = 135) was protective from death both in unadjusted and adjusted models [OR 0.157 (CI95% 0.026-0.945), p = 0.043. CONCLUSIONS: In a COVID-19 department the severity of pneumonia that did not differ between Omicron-1 and Delta variants predicted mortality whilst remdesivir remained protective in all analyses. Death rates did not differ between SARS-CoV-2 variants. Vigilance and consistency with prevention and treatment guidelines for COVID-19 is mandatory regardless of the predominant SARS-CoV-2 variant.


Asunto(s)
COVID-19 , Neumonía , Humanos , Masculino , Anciano , SARS-CoV-2 , Obesidad
5.
Blood ; 115(22): 4517-23, 2010 Jun 03.
Artículo en Inglés | MEDLINE | ID: mdl-20304805

RESUMEN

The 46/1 JAK2 haplotype predisposes to V617F-positive myeloproliferative neoplasms, but the underlying mechanism is obscure. We analyzed essential thrombocythemia patients entered into the PT-1 studies and, as expected, found that 46/1 was overrepresented in V617F-positive cases (n = 404) versus controls (n = 1492, P = 3.9 x 10(-11)). The 46/1 haplotype was also overrepresented in cases without V617F (n = 347, P = .009), with an excess seen for both MPL exon 10 mutated and V617F, MPL exon 10 nonmutated cases. Analysis of further MPL-positive, V617F-negative cases confirmed an excess of 46/1 (n = 176, P = .002), but no association between MPL mutations and MPL haplotype was seen. An excess of 46/1 was also seen in JAK2 exon 12 mutated cases (n = 69, P = .002), and these mutations preferentially arose on the 46/1 chromosome (P = .029). No association between 46/1 and clinical or laboratory features was seen in the PT-1 cohort either with or without V617F. The excess of 46/1 in JAK2 exon 12 cases is compatible with both the "hypermutability" and "fertile ground" hypotheses, but the excess in MPL-mutated cases argues against the former. No difference in sequence, splicing, or expression of JAK2 was found on 46/1 compared with other haplotypes, suggesting that any functional difference of JAK2 on 46/1, if it exists, must be relatively subtle.


Asunto(s)
Janus Quinasa 2/genética , Mutación , Trastornos Mieloproliferativos/genética , Receptores de Trombopoyetina/genética , Adulto , Anciano , Sustitución de Aminoácidos , Secuencia de Bases , Estudios de Casos y Controles , Estudios de Cohortes , Cartilla de ADN/genética , Exones , Femenino , Frecuencia de los Genes , Predisposición Genética a la Enfermedad , Haplotipos , Humanos , Desequilibrio de Ligamiento , Masculino , Persona de Mediana Edad , Modelos Genéticos , Mutación Missense , Policitemia Vera/genética , Polimorfismo de Nucleótido Simple , Estudios Prospectivos , Trombocitemia Esencial/tratamiento farmacológico , Trombocitemia Esencial/genética
6.
Blood ; 116(22): e111-7, 2010 Nov 25.
Artículo en Inglés | MEDLINE | ID: mdl-20720184

RESUMEN

Serial quantitation of BCR-ABL mRNA levels is an important indicator of therapeutic response for patients with chronic myelogenous leukemia and Philadelphia chromosome-positive acute lymphoblastic leukemia, but there is substantial variation in the real-time quantitative polymerase chain reaction methodologies used by different testing laboratories. To help improve the comparability of results between centers we sought to develop accredited reference reagents that are directly linked to the BCR-ABL international scale. After assessment of candidate cell lines, a reference material panel comprising 4 different dilution levels of freeze-dried preparations of K562 cells diluted in HL60 cells was prepared. After performance evaluation, the materials were assigned fixed percent BCR-ABL/control gene values according to the International Scale. A recommendation that the 4 materials be established as the first World Health Organization International Genetic Reference Panel for quantitation of BCR-ABL translocation by real-time quantitative polymerase chain reaction was approved by the Expert Committee on Biological Standardization of the World Health Organization in November 2009. We consider that the development of these reagents is a significant milestone in the standardization of this clinically important test, but because they are a limited resource we suggest that their availability is restricted to manufacturers of secondary reference materials.


Asunto(s)
Proteínas de Fusión bcr-abl/genética , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , ARN Mensajero/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa/normas , Línea Celular , Humanos , Estándares de Referencia , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa/métodos , Organización Mundial de la Salud
7.
Microbiol Spectr ; 10(6): e0213422, 2022 12 21.
Artículo en Inglés | MEDLINE | ID: mdl-36409093

RESUMEN

The first SARS-CoV-2 case in Greece was confirmed on February 26, 2020, and since then, multiple strains have circulated the country, leading to regional and country-wide outbreaks. Our aim is to enlighten the events that took place during the first days of the SARS-CoV-2 pandemic in Greece, focusing on the role of the first imported group of travelers. We used whole-genome SARS-CoV-2 sequences obtained from the infected travelers of the group as well as Greece-derived and globally subsampled sequences and applied dedicated phylogenetics and phylodynamics tools as well as in-house-developed bioinformatics pipelines. Our analyses reveal the genetic variants circulating in Greece during the first days of the pandemic and the role of the group's imported strains in the course of the first pandemic wave in Greece. The strain that dominated in Greece throughout the first wave, bearing the D614G mutation, was primarily imported from a certain group of travelers, while molecular and clinical data suggest that the infection of the travelers occurred in Egypt. Founder effects early in the pandemic are important for the success of certain strains, as those arriving early, several times, and to diverse locations lead to the formation of large transmission clusters that can be estimated using molecular epidemiology approaches and can be a useful surveillance tool for the prioritization of nonpharmaceutical interventions and combating present and future outbreaks. IMPORTANCE The strain that dominated in Greece during the first pandemic wave was primarily imported from a group of returning travelers in February 2020, while molecular and clinical data suggest that the origin of the transmission was Egypt. The observed molecular transmission clusters reflect the transmission dynamics of this particular strain bearing the D614G mutation while highlighting the necessity of their use as a surveillance tool for the prioritization of nonpharmaceutical interventions and combating present and future outbreaks.


Asunto(s)
COVID-19 , Humanos , COVID-19/epidemiología , Grecia/epidemiología , Pandemias , SARS-CoV-2/genética , Brotes de Enfermedades
8.
Leuk Lymphoma ; 63(3): 729-737, 2022 03.
Artículo en Inglés | MEDLINE | ID: mdl-34738857

RESUMEN

Ribonucleotide Reductase (RNR) is a two-subunit (RRM1, RRM2) enzyme, responsible for the conversion of ribonucleotides to deoxyribonucleotides required for DNA replication. To evaluate RNR as a biomarker of response to 5-azacytidine, we measured RNR mRNA levels by a quantitative real-time PCR in bone marrow samples of 98 patients with myelodysplastic syndrome (MDS) treated with 5-azacytidine with parallel quantification of the gene promoter's methylation. Patients with low RRM1 levels had a high RRM1 methylation status (p = 0.005) and a better response to treatment with 5-azacytidine (p = 0.019). A next-generation sequencing for genes of interest in MDS was also carried out in a subset of 61 samples. Splicing factor mutations were correlated with lower RRM1 mRNA levels (p = 0.044). Our results suggest that the expression of RNR is correlated with clinical outcomes, thus its expression could be used as a prognostic factor for response to 5-azacytidine and a possible therapeutic target in MDS.


Asunto(s)
Síndromes Mielodisplásicos , Ribonucleótido Reductasas , Azacitidina/farmacología , Azacitidina/uso terapéutico , Médula Ósea/metabolismo , Humanos , Metilación , Síndromes Mielodisplásicos/diagnóstico , Síndromes Mielodisplásicos/tratamiento farmacológico , Síndromes Mielodisplásicos/genética , Pronóstico , ARN Mensajero/genética , ARN Mensajero/metabolismo , Ribonucleósido Difosfato Reductasa/genética , Ribonucleósido Difosfato Reductasa/metabolismo , Ribonucleótido Reductasas/genética
9.
Blood ; 113(24): 6182-92, 2009 Jun 11.
Artículo en Inglés | MEDLINE | ID: mdl-19387008

RESUMEN

Recent evidence has demonstrated that acquired uniparental disomy (aUPD) is a novel mechanism by which pathogenetic mutations in cancer may be reduced to homozygosity. To help identify novel mutations in myeloproliferative neoplasms (MPNs), we performed a genome-wide single nucleotide polymorphism (SNP) screen to identify aUPD in 58 patients with atypical chronic myeloid leukemia (aCML; n = 30), JAK2 mutation-negative myelofibrosis (MF; n = 18), or JAK2 mutation-negative polycythemia vera (PV; n = 10). Stretches of homozygous, copy neutral SNP calls greater than 20Mb were seen in 10 (33%) aCML and 1 (6%) MF, but were absent in PV. In total, 7 different chromosomes were involved with 7q and 11q each affected in 10% of aCML cases. CBL mutations were identified in all 3 cases with 11q aUPD and analysis of 574 additional MPNs revealed a total of 27 CBL variants in 26 patients with aCML, myelofibrosis or chronic myelomonocytic leukemia. Most variants were missense substitutions in the RING or linker domains that abrogated CBL ubiquitin ligase activity and conferred a proliferative advantage to 32D cells overexpressing FLT3. We conclude that acquired, transforming CBL mutations are a novel and widespread pathogenetic abnormality in morphologically related, clinically aggressive MPNs.


Asunto(s)
Cromosomas Humanos Par 11/genética , Mutación Missense/genética , Trastornos Mieloproliferativos/genética , Polimorfismo de Nucleótido Simple/genética , Proteínas Proto-Oncogénicas c-cbl/genética , Disomía Uniparental/genética , Empalme Alternativo , Secuencia de Aminoácidos , Genoma Humano , Estudio de Asociación del Genoma Completo , Humanos , Janus Quinasa 2/genética , Janus Quinasa 2/metabolismo , Repeticiones de Microsatélite , Datos de Secuencia Molecular , Células Mieloides/metabolismo , Células Mieloides/patología , Pronóstico , Homología de Secuencia de Aminoácido , Tasa de Supervivencia , Tirosina Quinasa 3 Similar a fms/antagonistas & inhibidores , Tirosina Quinasa 3 Similar a fms/genética , Tirosina Quinasa 3 Similar a fms/metabolismo
10.
Haematologica ; 95(9): 1473-80, 2010 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-20421268

RESUMEN

BACKGROUND: Aberrant activation of tyrosine kinases, caused by either mutation or gene fusion, is of major importance for the development of many hematologic malignancies, particularly myeloproliferative neoplasms. We hypothesized that hitherto unrecognized, cytogenetically cryptic tyrosine kinase fusions may be common in non-classical or atypical myeloproliferative neoplasms and related myelodysplastic/myeloproliferative neoplasms. DESIGN AND METHODS: To detect genomic copy number changes associated with such fusions, we performed a systematic search in 68 patients using custom designed, targeted, high-resolution array comparative genomic hybridization. Arrays contained 44,000 oligonucleotide probes that targeted 500 genes including all 90 tyrosine kinases plus downstream tyrosine kinase signaling components, other translocation targets, transcription factors, and other factors known to be important for myelopoiesis. RESULTS: No abnormalities involving tyrosine kinases were detected; however, nine cytogenetically cryptic copy number imbalances were detected in seven patients, including hemizygous deletions of RUNX1 or CEBPA in two cases with atypical chronic myeloid leukemia. Mutation analysis of the remaining alleles revealed non-mutated RUNX1 and a frameshift insertion within CEBPA. A further mutation screen of 187 patients with myelodysplastic/myeloproliferative neoplasms identified RUNX1 mutations in 27 (14%) and CEBPA mutations in seven (4%) patients. Analysis of other transcription factors known to be frequently mutated in acute myeloid leukemia revealed NPM1 mutations in six (3%) and WT1 mutations in two (1%) patients with myelodysplastic/myeloproliferative neoplasms. Univariate analysis indicated that patients with mutations had a shorter overall survival (28 versus 44 months, P=0.019) compared with patients without mutations, with the prognosis for cases with CEBPA, NPM1 or WT1 mutations being particularly poor. CONCLUSIONS: We conclude that mutations of transcription and other nuclear factors are frequent in myelodysplastic/myeloproliferative neoplasms and are generally mutually exclusive. CEBPA, NPM1 or WT1 mutations may be associated with a poor prognosis, an observation that will need to be confirmed by detailed prospective studies.


Asunto(s)
Mutación , Síndromes Mielodisplásicos/genética , Trastornos Mieloproliferativos/genética , Factores de Transcripción/genética , Proteínas Potenciadoras de Unión a CCAAT/genética , Hibridación Genómica Comparativa , Análisis Mutacional de ADN , Dosificación de Gen , Humanos , Leucemia Mielógena Crónica BCR-ABL Positiva , Mielopoyesis/genética , Proteínas Nucleares/genética , Nucleofosmina , Pronóstico , Proteínas WT1/genética
11.
Leuk Res ; 33(1): 67-73, 2009 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-18632151

RESUMEN

A systematic review and meta-analysis was carried out to compare the frequency of clinically significant outcomes between JAK2 V617F positive and wild type patients with essential thrombocythemia (ET). JAK2 V617F positivity in patients with ET was associated with a clear increase in the odds of thrombosis [OR=1.83 (95% CI, 1.32-2.53), p<0.0001], and much higher odds of transformation to polycythemia vera [OR=7.67 (95% CI, 2.04-28.87), p=0.0009]. The mean difference of the white blood cell count between JAK2 positive and negative patients was associated with an increased odds ratio for thrombosis (p=0.02). The JAK2 V617F mutation in patients with ET is associated with an increased risk of adverse cardiovascular outcomes via an increase in the leukocyte count.


Asunto(s)
Janus Quinasa 2/genética , Mutación , Policitemia Vera/patología , Trombocitemia Esencial/patología , División Celular , Células Madre Hematopoyéticas/patología , Humanos , Policitemia Vera/genética , Estudios Retrospectivos , Trombocitemia Esencial/genética
12.
Leukemia ; 33(5): 1184-1194, 2019 05.
Artículo en Inglés | MEDLINE | ID: mdl-30573780

RESUMEN

Acquired uniparental disomy (aUPD, also known as copy-neutral loss of heterozygosity) is a common feature of cancer cells and characterized by extended tracts of somatically-acquired homozygosity without any concurrent loss or gain of genetic material. The presumed genetic targets of many regions of aUPD remain unknown. Here we describe the association of chromosome 22 aUPD with mutations that delete the C-terminus of PRR14L in patients with chronic myelomonocytic leukemia (CMML), related myeloid neoplasms and age-related clonal hematopoiesis (ARCH). Myeloid panel analysis identified a median of three additional mutated genes (range 1-6) in cases with a myeloid neoplasm (n = 8), but no additional mutations in cases with ARCH (n = 2) suggesting that mutated PRR14L alone may be sufficient to drive clonality. PRR14L has very limited homology to other proteins and its function is unknown. ShRNA knockdown of PRR14L in human CD34+ cells followed by in vitro growth and differentiation assays showed an increase in monocytes and decrease in neutrophils, consistent with a CMML-like phenotype. RNA-Seq and cellular localization studies suggest a role for PRR14L in cell division. PRR14L is thus a novel, biallelically mutated gene and potential founding abnormality in myeloid neoplasms.


Asunto(s)
Proteínas Cromosómicas no Histona/genética , Cromosomas Humanos Par 22 , Hematopoyesis/genética , Mutación , Trastornos Mieloproliferativos/genética , Disomía Uniparental , Diferenciación Celular/genética , Femenino , Técnica del Anticuerpo Fluorescente , Regulación Leucémica de la Expresión Génica , Técnicas de Silenciamiento del Gen , Técnicas de Inactivación de Genes , Humanos , Masculino , Trastornos Mieloproliferativos/diagnóstico , Fenotipo , Polimorfismo de Nucleótido Simple , Secuenciación del Exoma
13.
Br J Haematol ; 141(1): 100-4, 2008 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-18324972

RESUMEN

CD177 (PRV1) expression is strongly related to polycythaemia vera (PV). Whilst studying CD177 expression in PV patients and controls, individuals with beta-thalassaemia minor were found to display an elevated expression of CD177. The study was expanded to include patients with thalassaemia intermedia, sickle cell/beta-thalassaemia and thalassaemia major. CD177 expression was increased in these thalassaemic groups and correlated with their erythropoietic activity, as assessed by the measurement of serum erythropoietin and soluble transferrin receptor levels. Within this context, elevated CD177 expression is not only a specific feature of PV but may be an indicator of increased erythropoietic activity in thalassaemia syndromes.


Asunto(s)
Eritropoyesis , Isoantígenos/biosíntesis , Glicoproteínas de Membrana/biosíntesis , Receptores de Superficie Celular/biosíntesis , Talasemia beta/sangre , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Eritropoyetina/sangre , Proteínas Ligadas a GPI , Expresión Génica , Genotipo , Humanos , Isoantígenos/genética , Janus Quinasa 2/genética , Glicoproteínas de Membrana/genética , Persona de Mediana Edad , Mutación , Policitemia Vera/sangre , Policitemia Vera/genética , ARN Mensajero/genética , Receptores de Superficie Celular/genética , Receptores de Transferrina/sangre , Talasemia beta/genética , Talasemia beta/fisiopatología
15.
Medicine (Baltimore) ; 86(6): 344-354, 2007 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-18004179

RESUMEN

Hypereosinophilic syndrome (HES) is a heterogeneous group of disorders characterized by unexplained persistent primary eosinophilia causing end-organ damage. We conducted a prospective cohort study of patients fulfilling the diagnostic criteria for HES. Of 20 patients considered eligible for the study, 2 were found to have clonal myeloid disorders, limiting the diagnosis of "true" HES to 18 patients. No patient carried the FIP1L1-PDGFRA fusion gene or other imatinib-responsive translocations. A clonal interleukin-5-producing T-cell population was not detected in any patient. Common manifestations at presentation were pulmonary, cutaneous, and neurologic involvement; serositis; and gastrointestinal involvement. Only 3 patients developed cardiac involvement. Fifteen of the HES patients were administered first-line combined treatment with steroids and hydroxyurea. Nine patients achieved complete response, while 6 attained only partial response. Imatinib was administered to 3 HES patients who had been pretreated with steroids, resulting in complete hematologic and clinical response in 2 patients and no response at all in 1. Further treatment of the latter patient with steroids and hydroxyurea also proved ineffective. We conclude that the therapeutic approach should be individualized according to molecular findings. We consider the coadministration of corticosteroids and hydroxyurea to be an effective combination for the treatment of FIP1L1-PDGFRA-negative HES.


Asunto(s)
Antineoplásicos/uso terapéutico , Síndrome Hipereosinofílico/diagnóstico , Síndrome Hipereosinofílico/tratamiento farmacológico , Proteínas de Fusión Oncogénica/genética , Selección de Paciente , Receptor alfa de Factor de Crecimiento Derivado de Plaquetas/genética , Factores de Escisión y Poliadenilación de ARNm/genética , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Benzamidas , Análisis Citogenético , Femenino , Humanos , Hidroxiurea/administración & dosificación , Síndrome Hipereosinofílico/genética , Mesilato de Imatinib , Masculino , Persona de Mediana Edad , Piperazinas/uso terapéutico , Prednisona/administración & dosificación , Estudios Prospectivos , Pirimidinas/uso terapéutico , Translocación Genética/genética
16.
Leuk Res ; 31(7): 1009-14, 2007 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-17204324

RESUMEN

We report a JAK2 V617F-negative case of polycythemia vera with two acquired balanced X-autosome translocations and no history of previous exposure to chemo/radiotherapy. The patient's first clone carried a novel translocation t(X;15)(q24;q13) as a sole abnormality. The second clone exhibited an additional translocation, t(X;20)(q13;q13.3), which is a rare recurrent abnormality in myeloid malignancies. This is the first report of a hematological disorder with both X chromosomes being translocated. Late replication studies revealed a switch in X-inactivation from the X chromosome involved in t(X;15) (first clone) to the X chromosome involved in the t(X;20)(q13;q13.3) (second clone). The inactivation of the translocated X chromosomes could provide potential for the inactivation of the adjacent autosomal regions, resulting in epigenetic gene silencing.


Asunto(s)
Trastornos de los Cromosomas/genética , Cromosomas Humanos Par 5/genética , Cromosomas Humanos X/genética , Janus Quinasa 2/genética , Policitemia Vera/genética , Translocación Genética , Inactivación del Cromosoma X/genética , Anciano , Trastornos de los Cromosomas/complicaciones , Femenino , Humanos , Hibridación Fluorescente in Situ
17.
J Clin Oncol ; 35(9): 947-954, 2017 Mar 20.
Artículo en Inglés | MEDLINE | ID: mdl-28297629

RESUMEN

Myeloproliferative neoplasms (MPNs) are a group of related clonal hematologic disorders characterized by excess accumulation of one or more myeloid cell lineages and a tendency to transform to acute myeloid leukemia. Deregulated JAK2 signaling has emerged as the central phenotypic driver of BCR -ABL1-negative MPNs and a unifying therapeutic target. In addition, MPNs show unexpected layers of genetic complexity, with multiple abnormalities associated with disease progression, interactions between inherited factors and phenotype driver mutations, and effects related to the order in which mutations are acquired. Although morphology and clinical laboratory analysis continue to play an important role in defining these conditions, genomic analysis is providing a platform for better disease definition, more accurate diagnosis, direction of therapy, and refined prognostication. There is an emerging consensus with regard to many prognostic factors, but there is a clear need to synthesize genomic findings into robust, clinically actionable and widely accepted scoring systems as well as the need to standardize the laboratory methodologies that are used.


Asunto(s)
Neoplasias Hematológicas/genética , Trastornos Mieloproliferativos/genética , Genómica/métodos , Humanos , Mutación
18.
Mediterr J Hematol Infect Dis ; 9(1): e2017066, 2017.
Artículo en Inglés | MEDLINE | ID: mdl-29181143

RESUMEN

Myeloid neoplasms with isolated isochromosome 17q [MN i(17q)] has been described as a distinct entity with poor prognosis. However, literature reports show a considerable clinical and molecular heterogeneity. We describe a 58-year-old male patient who was diagnosed as refractory anemia with multilineage dysplasia and ringed sideroblasts with isolated i(17q). Though he initially responded well to erythropoietin, he gradually progressed to an aggressive form of MDS/MPN refractory to azacytidine and died 29 months after the first diagnosis. Notably, in contrast to disease advancement, his karyotype reverted to normal, whereas his mutational profile remained unchanged. To our knowledge, this is the first report of karyotype normalization during disease progression in patients with MN i(17q). It suggests that the i(17q) anomaly is dispensable for the leukemic transformation and highlighting the underlying clinical and molecular complexity which both has to be resolved before the establishment of MN with isolated i(17q) as a distinct entity.

19.
Int J Hematol ; 101(3): 229-42, 2015 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-25212680

RESUMEN

According to the 2008 WHO classification, the category of myelodysplastic/myeloproliferative neoplasms (MDS/MPN) includes atypical chronic myeloid leukaemia (aCML), chronic myelomonocytic leukaemia (CMML), MDS/MPN-unclassifiable (MDS/MPN-U), juvenile myelomonocytic leukaemia (JMML) and a "provisional" entity, refractory anaemia with ring sideroblasts and thrombocytosis (RARS-T). The remarkable progress in our understanding of the somatic pathogenesis of MDS/MPN has made it clear that there is considerable overlap among these diseases at the molecular level, as well as layers of unexpected complexity. Deregulation of signalling plays an important role in many cases, and is clearly linked to more highly proliferative disease. Other mutations affect a range of other essential, interrelated cellular mechanisms, including epigenetic regulation, RNA splicing, transcription, and DNA damage response. The various combinations of mutations indicate a multi-step pathogenesis, which likely contributes to the marked clinical heterogeneity of these disorders. The delineation of complex clonal architectures may serve as the cornerstone for the identification of novel therapeutic targets and lead to better patient outcomes. This review summarizes some of the current knowledge of molecular pathogenetic lesions in the MDS/MPN subtypes that are seen in adults: atypical CML, CMML and MDS/MPN-U.


Asunto(s)
Leucemia Mieloide Crónica Atípica BCR-ABL Negativa/genética , Leucemia Mielomonocítica Crónica/genética , Enfermedades Mielodisplásicas-Mieloproliferativas/genética , Animales , Análisis Citogenético , Daño del ADN , Epigénesis Genética , Regulación Neoplásica de la Expresión Génica , Humanos , Leucemia Mieloide Crónica Atípica BCR-ABL Negativa/metabolismo , Leucemia Mieloide Crónica Atípica BCR-ABL Negativa/patología , Leucemia Mielomonocítica Crónica/metabolismo , Leucemia Mielomonocítica Crónica/patología , Mutación , Enfermedades Mielodisplásicas-Mieloproliferativas/clasificación , Enfermedades Mielodisplásicas-Mieloproliferativas/metabolismo , Enfermedades Mielodisplásicas-Mieloproliferativas/patología , Empalme del ARN , Transducción de Señal
20.
Nat Commun ; 6: 6691, 2015 Apr 07.
Artículo en Inglés | MEDLINE | ID: mdl-25849990

RESUMEN

Clonal proliferation in myeloproliferative neoplasms (MPN) is driven by somatic mutations in JAK2, CALR or MPL, but the contribution of inherited factors is poorly characterized. Using a three-stage genome-wide association study of 3,437 MPN cases and 10,083 controls, we identify two SNPs with genome-wide significance in JAK2(V617F)-negative MPN: rs12339666 (JAK2; meta-analysis P=1.27 × 10(-10)) and rs2201862 (MECOM; meta-analysis P=1.96 × 10(-9)). Two additional SNPs, rs2736100 (TERT) and rs9376092 (HBS1L/MYB), achieve genome-wide significance when including JAK2(V617F)-positive cases. rs9376092 has a stronger effect in JAK2(V617F)-negative cases with CALR and/or MPL mutations (Breslow-Day P=4.5 × 10(-7)), whereas in JAK2(V617F)-positive cases rs9376092 associates with essential thrombocythemia (ET) rather than polycythemia vera (allelic χ(2) P=7.3 × 10(-7)). Reduced MYB expression, previously linked to development of an ET-like disease in model systems, associates with rs9376092 in normal myeloid cells. These findings demonstrate that multiple germline variants predispose to MPN and link constitutional differences in MYB expression to disease phenotype.


Asunto(s)
Policitemia Vera/genética , Trombocitemia Esencial/genética , Adulto , Anciano , Alelos , Calreticulina/genética , Estudios de Casos y Controles , Estudios de Cohortes , Proteínas de Unión al ADN/genética , Femenino , Proteínas de Unión al GTP/genética , Frecuencia de los Genes , Genes myb/genética , Predisposición Genética a la Enfermedad , Variación Genética , Genotipo , Proteínas HSP70 de Choque Térmico/genética , Humanos , Janus Quinasa 2/genética , Proteína del Locus del Complejo MDS1 y EV11 , Masculino , Persona de Mediana Edad , Mutación , Trastornos Mieloproliferativos/genética , Factores de Elongación de Péptidos/genética , Polimorfismo de Nucleótido Simple , Proto-Oncogenes/genética , Receptores de Trombopoyetina/genética , Telomerasa/genética , Factores de Transcripción/genética
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