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1.
Blood Adv ; 3(22): 3579-3589, 2019 Nov 26.
Artigo em Inglês | MEDLINE | ID: mdl-31738830

RESUMO

Myelodysplastic syndromes (MDS) are hematopoietic stem cell malignancies. Known predisposing factors to adult MDS include rare germline mutations, cytotoxic therapy, age-related clonal hematopoiesis, and autoimmune or chronic inflammatory disorders. To date, no published studies characterizing MDS-associated germline susceptibility polymorphisms exist. We performed a genome-wide association study of 2 sample sets (555 MDS cases vs 2964 control subjects; 352 MDS cases vs 2640 control subjects) in non-del(5q) MDS cases of European genomic ancestry. Meta-analysis identified 8 MDS-associated loci at 1q31.1 (PLA2G4A), 3p14.1 (FAM19A4), 5q21.3 (EFNA5), 6p21.33, 10q23.1 (GRID1), 12q24.32, 15q26.1, and 20q13.12 (EYA2) that approached genome-wide significance. Gene expression for 5 loci that mapped within or near genes was significantly upregulated in MDS bone marrow cells compared with those of control subjects (P < .01). Higher PLA2G4A expression and lower EYA2 expression were associated with poorer overall survival (P = .039 and P = .037, respectively). Higher PLA2G4A expression is associated with mutations in NRAS (P < .001), RUNX1 (P = .012), ASXL1 (P = .007), and EZH2 (P = .038), all of which are known to contribute to MDS development. EYA2 expression was an independently favorable risk factor irrespective of age, sex, and Revised International Scoring System score (relative risk, 0.67; P = .048). Notably, these genes have regulatory roles in innate immunity, a critical driver of MDS pathogenesis. EYA2 overexpression induced innate immune activation, whereas EYA2 inhibition restored colony-forming potential in primary MDS cells indicative of hematopoietic restoration and possible clinical relevance. In conclusion, among 8 suggestive MDS-associated loci, 5 map to genes upregulated in MDS with functional roles in innate immunity and potential biological relevance to MDS.

2.
Histol Histopathol ; 34(8): 857-873, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30779051

RESUMO

The diagnosis of myelodysplastic syndromes is based on the presence of cytopenias, dysplastic morphological features on peripheral blood (PB) and bone marrow (BM), cytogenetic abnormalities and requires to rule out other diseases resembling these conditions. Optical cytomorphology is the cornerstone of diagnosis of MDS. The recognition of cytological myelodysplasia has a crucial value in diagnosis and prognosis of MDS. Assessment of cytological morphology requires, like other diagnostic techniques (flow cytometry, cytogenetics, histological morphology), experienced observers and the availability of high quality and properly stained samples. The morphological analysis has shown moderate reproducibility among hematopathologists. The better characterization and standardization of morphological features has improved the reliability and reproducibility of MDS diagnosis. Maintaining the competence in morphology assessment requires experience and continuous training. For the correct assessment of cytologic myelodysplasia it is essential to keep in mind the morphology of normal myelopoiesis. To the extent of our knowledge there are no studies describing together morphological data on normal and dysplastic myelopoiesis in the framework of MDS. Therefore, by combining these data, this manuscript could serve as a useful tool for quotidian process of diagnosis.


Assuntos
Síndromes Mielodisplásicas/diagnóstico , Síndromes Mielodisplásicas/fisiopatologia , Mielopoese , Células Sanguíneas/patologia , Medula Óssea/patologia , Citogenética , Citometria de Fluxo , Humanos , Microscopia
3.
Haematologica ; 104(4): 778-788, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-29954928

RESUMO

Constitutive activation of the chemokine receptor CXCR4 has been associated with tumor progression, invasion, and chemotherapy resistance in different cancer subtypes. Although the CXCR4 pathway has recently been suggested as an adverse prognostic marker in diffuse large B-cell lymphoma, its biological relevance in this disease remains underexplored. In a homogeneous set of 52 biopsies from patients, an antibody-based cytokine array showed that tissue levels of CXCL12 correlated with high microvessel density and bone marrow involvement at diagnosis, supporting a role for the CXCL12-CXCR4 axis in disease progression. We then identified the tetra-amine IQS-01.01RS as a potent inverse agonist of the receptor, preventing CXCL12-mediated chemotaxis and triggering apoptosis in a panel of 18 cell lines and primary cultures, with superior mobilizing properties in vivo than those of the standard agent. IQS-01.01RS activity was associated with downregulation of p-AKT, p-ERK1/2 and destabilization of MYC, allowing a synergistic interaction with the bromodomain and extra-terminal domain inhibitor, CPI203. In a xenotransplant model of diffuse large B-cell lymphoma, the combination of IQS-01.01RS and CPI203 decreased tumor burden through MYC and p-AKT downregulation, and enhanced the induction of apoptosis. Thus, our results point out an emerging role of CXCL12-CXCR4 in the pathogenesis of diffuse large B-cell lymphoma and support the simultaneous targeting of CXCR4 and bromodomain proteins as a promising, rationale-based strategy for the treatment of this disease.

4.
Haematologica ; 103(12): 2008-2015, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30026338

RESUMO

YARS2 variants have previously been described in patients with myopathy, lactic acidosis and sideroblastic anemia 2 (MLASA2). YARS2 encodes the mitochondrial tyrosyl-tRNA synthetase, which is responsible for conjugating tyrosine to its cognate mt-tRNA for mitochondrial protein synthesis. Here we describe 14 individuals from 11 families presenting with sideroblastic anemia and YARS2 variants that we identified using a sideroblastic anemia gene panel or exome sequencing. The phenotype of these patients ranged from MLASA to isolated congenital sideroblastic anemia. As in previous cases, inter- and intra-familial phenotypic variability was observed, however, this report includes the first cases with isolated sideroblastic anemia and patients with biallelic YARS2 variants that have no clinically ascertainable phenotype. We identified ten novel YARS2 variants and three previously reported variants. In vitro amino-acylation assays of five novel missense variants showed that three had less effect on the catalytic activity of YARS2 than the most commonly reported variant, p.(Phe52Leu), associated with MLASA2, which may explain the milder phenotypes in patients with these variants. However, the other two missense variants had a more severe effect on YARS2 catalytic efficiency. Several patients carried the common YARS2 c.572 G>T, p.(Gly191Val) variant (minor allele frequency =0.1259) in trans with a rare deleterious YARS2 variant. We have previously shown that the p.(Gly191Val) variant reduces YARS2 catalytic activity. Consequently, we suggest that biallelic YARS2 variants, including severe loss-of-function alleles in trans of the common p.(Gly191Val) variant, should be considered as a cause of isolated congenital sideroblastic anemia, as well as the MLASA syndromic phenotype.


Assuntos
Acidose Láctica/genética , Anemia Sideroblástica/genética , Doenças Genéticas Ligadas ao Cromossomo X/genética , Mutação em Linhagem Germinativa , Síndrome MELAS/genética , Proteínas Mitocondriais/genética , Tirosina-tRNA Ligase/genética , Acidose Láctica/enzimologia , Adolescente , Anemia Sideroblástica/enzimologia , Feminino , Estudos de Associação Genética , Doenças Genéticas Ligadas ao Cromossomo X/enzimologia , Humanos , Lactente , Síndrome MELAS/enzimologia , Masculino , Pessoa de Meia-Idade , Mutação de Sentido Incorreto , Adulto Jovem
5.
J Clin Pathol ; 71(11): 975-980, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-29934356

RESUMO

AIM: To characterise the clinical and histological features of MPL-mutated essential thrombocythaemia (ET). PATIENTS AND METHODS: Bone marrow biopsies of 175 patients with ET were centrally reviewed according to the 2016 WHO classification, including 42 cases with MPL mutation, 98 JAK2V617F-mutated and 35 CALR-mutated. Clinical and histological features were compared among the three genotypes included in the current 2016 WHO classification and among the different types of MPL mutations. RESULTS: Patients with MPL-mutated ET were significantly older than those with the other genotypes. Haematological values at diagnosis were similar among MPL-mutated and CALR-mutated ET, with both genotypes showing higher platelet counts and lower haemoglobin values than ET with JAK2V617F genotype. In the bone marrow, the median number of megakaryocytes was higher in MPL and CALR than in JAK2V617F genotype (16, 19 and 14 megakaryocytes per ×20 power field, respectively, p=0.004). Histological features of prefibrotic myelofibrosis were rarely observed in MPL genotype, whereas sinusoidal hyperplasia, dense clusters of megakaryocytes and reticulin fibrosis were more frequent in CALR-mutated ET, with 11% of such cases fulfilling WHO 2016 histological criteria of prefibrotic myelofibrosis. With a median follow-up of 3.5 years, no significant differences were seen among genotypes regarding survival, vascular complications or myelofibrotic transformation. There were no significant differences in the clinical data or in the histological characteristics depending on the type of MPL mutation. CONCLUSION: MPL and CALR ET genotypes share clinical and histological characteristics. In contrast to CALR genotype, features of prefibrotic myelofibrosis are uncommon in MPL-mutated ET.


Assuntos
Calreticulina/genética , Janus Quinase 2/genética , Mutação , Mielofibrose Primária/genética , Receptores de Trombopoetina/genética , Trombocitemia Essencial/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Biópsia , Exame de Medula Óssea , Proliferação de Células , Criança , Análise Mutacional de DNA , Feminino , Marcadores Genéticos , Predisposição Genética para Doença , Hemoglobinas/análise , Humanos , Masculino , Megacariócitos/patologia , Pessoa de Meia-Idade , Fenótipo , Contagem de Plaquetas , Mielofibrose Primária/sangue , Mielofibrose Primária/patologia , Prognóstico , Trombocitemia Essencial/sangue , Trombocitemia Essencial/patologia , Adulto Jovem
7.
Am J Hematol ; 92(9): E534-E541, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28612357

RESUMO

The International Prognostic Scoring System and its revised form (IPSS-R) are the most widely used indices for prognostic assessment of patients with myelodysplastic syndromes (MDS), but can only partially account for the observed variation in patient outcomes. This study aimed to evaluate the relative contribution of patient condition and mutational status in peripheral blood when added to the IPSS-R, for estimating overall survival and the risk of leukemic transformation in patients with MDS. A prospective cohort (2006-2015) of 200 consecutive patients with MDS were included in the study series and categorized according to the IPSS-R. Patients were further stratified according to patient condition (assessed using the multidimensional Lee index for older adults) and genetic mutations (peripheral blood samples screened using next-generation sequencing). The change in likelihood-ratio was tested in Cox models after adding individual covariates. The addition of the Lee index to the IPSS-R significantly improved prediction of overall survival [hazard ratio (HR) 3.02, 95% confidence interval (CI) 1.96-4.66, P < 0.001), and mutational analysis significantly improved prediction of leukemic evolution (HR 2.64, 1.56-4.46, P < 0.001). Non-leukemic death was strongly linked to patient condition (HR 2.71, 1.72-4.25, P < 0.001), but not to IPSS-R score (P = 0.35) or mutational status (P = 0.75). Adjustment for exposure to disease-modifying therapy, evaluated as a time-dependent covariate, had no effect on the proposed model's predictive ability. In conclusion, patient condition, assessed by the multidimensional Lee index and patient mutational status can improve the prediction of clinical outcomes of patients with MDS already stratified by IPSS-R.


Assuntos
Síndromes Mielodisplásicas/sangue , Síndromes Mielodisplásicas/genética , Síndromes Mielodisplásicas/mortalidade , Taxa de Sobrevida , Intervalo Livre de Doença , Feminino , Seguimentos , Humanos , Masculino , Estudos Prospectivos , Espanha/epidemiologia
8.
Am J Hematol ; 92(7): 614-621, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28370234

RESUMO

The Revised International Prognostic Scoring System (IPSS-R) has been recognized as the score with the best outcome prediction capability in MDS, but this brought new concerns about the accurate prognostication of patients classified into the intermediate risk category. The correct enumeration of blasts is essential in prognostication of MDS. Recent data evidenced that considering blasts from nonerythroid cellularity (NECs) improves outcome prediction in the context of IPSS and WHO classification. We assessed the percentage of blasts from total nucleated cells (TNCs) and NECs in 3924 MDS patients from the GESMD, 498 of whom were MDS with erythroid predominance (MDS-E). We assessed if calculating IPSS-R by enumerating blasts from NECs improves prognostication of MDS. Twenty-four percent of patients classified into the intermediate category were reclassified into higher-risk categories and showed shorter overall survival (OS) and time to AML evolution than those who remained into the intermediate one. Likewise, a better distribution of patients was observed, since lower-risk patients showed longer survivals than previously whereas higher-risk ones maintained the outcome expected in this poor prognostic group (median OS < 20 months). Furthermore, our approach was particularly useful for detecting patients at risk of dying with AML. Regarding MDS-E, 51% patients classified into the intermediate category were reclassified into higher-risk ones and showed shorter OS and time to AML. In this subgroup of MDS, IPSS-R was capable of splitting our series in five groups with significant differences in OS only when blasts were assessed from NECs. In conclusion, our easy-applicable approach improves prognostic assessment of MDS patients.


Assuntos
Medula Óssea/patologia , Síndromes Mielodisplásicas/diagnóstico , Síndromes Mielodisplásicas/mortalidade , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores , Terapia Combinada , Feminino , Humanos , Estimativa de Kaplan-Meier , Contagem de Leucócitos , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/terapia , Prognóstico , Modelos de Riscos Proporcionais , Resultado do Tratamento , Adulto Jovem
9.
Haematologica ; 102(6): 1099-1104, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-28255016

RESUMO

The presence of circulating plasma cells in patients with multiple myeloma is considered a marker for highly proliferative disease. In the study herein, the impact of circulating plasma cells assessed by cytology on survival of patients with multiple myeloma was analyzed. Wright-Giemsa stained peripheral blood smears of 482 patients with newly diagnosed myeloma or plasma cell leukemia were reviewed and patients were classified into 4 categories according to the percentage of circulating plasma cells: 0%, 1-4%, 5-20%, and plasma cell leukemia with the following frequencies: 382 (79.2%), 83 (17.2%), 12 (2.5%) and 5 (1.0%), respectively. Median overall survival according to the circulating plasma cells group was 47, 50, 6 and 14 months, respectively. At multivariate analysis, the presence of 5 to 20% circulating plasma cells was associated with a worse overall survival (relative risk 4.9, 95% CI 2.6-9.3) independently of age, creatinine, the Durie-Salmon system stage and the International Staging System (ISS) stage. Patients with ≥5% circulating plasma cells had lower platelet counts (median 86×109/L vs 214×109/L, P<0.0001) and higher bone marrow plasma cells (median 53% vs 36%, P=0.004). The presence of ≥5% circulating plasma cells in patients with multiple myeloma has a similar adverse prognostic impact as plasma cell leukemia.


Assuntos
Mieloma Múltiplo/diagnóstico , Plasmócitos/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Medula Óssea/patologia , Humanos , Leucemia Plasmocitária/diagnóstico , Leucemia Plasmocitária/mortalidade , Pessoa de Meia-Idade , Mieloma Múltiplo/patologia , Contagem de Plaquetas , Prognóstico , Estudos Retrospectivos , Análise de Sobrevida
11.
Mod Pathol ; 29(12): 1541-1551, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27562492

RESUMO

Erythroleukemia was considered an acute myeloid leukemia in the 2008 World Health Organization (WHO) classification and is defined by the presence of ≥50% bone marrow erythroblasts, having <20% bone marrow blasts from total nucleated cells but ≥20% bone marrow myeloblasts from nonerythroid cells. Erythroleukemia shares clinicopathologic features with myelodysplastic syndromes, especially with erythroid-predominant myelodysplastic syndromes (≥50% bone marrow erythroblasts). The upcoming WHO revision proposes to eliminate the nonerythroid blast cell count rule and to move erythroleukemia patients into the appropriate myelodysplastic syndrome category on the basis of the absolute blast cell count. We conducted a retrospective study of patients with de novo erythroleukemia and compared their clinico-biological features and outcome with those of de novo myelodysplastic syndromes, focusing on erythroid-predominant myelodysplastic syndromes. Median overall survival of 405 erythroid-predominant myelodysplastic syndromes without excess blasts was significantly longer than that observed in 57 erythroid-predominant refractory anemias with excess blasts-1 and in 59 erythroleukemias, but no significant difference was observed between erythroid-predominant refractory anemias with excess blasts-1 and erythroleukemias. In this subset of patients with ≥50% bone marrow erythroblasts and excess blasts, the presence of a high-risk karyotype defined by the International Prognostic Scoring System or by the Revised International Prognostic Scoring System was the main prognostic factor. In the same way, the survival of 459 refractory anemias with excess blasts-2, independently of having ≥20% bone marrow blasts from nonerythroid cells or not, was almost identical to the observed in 59 erythroleukemias. Interestingly, 11 low-blast count erythroleukemias with 5 to <10% bone marrow blasts from total nucleated cells showed similar survival than the rest of erythroleukemias. Our data suggest that de novo erythroleukemia is in the spectrum of myelodysplastic syndromes with excess blasts and support its inclusion into future classifications of myelodysplastic syndromes.


Assuntos
Leucemia Eritroblástica Aguda/classificação , Leucemia Eritroblástica Aguda/patologia , Síndromes Mielodisplásicas/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Estimativa de Kaplan-Meier , Leucemia Eritroblástica Aguda/mortalidade , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/mortalidade , Estudos Retrospectivos
12.
J Clin Oncol ; 34(27): 3284-92, 2016 09 20.
Artigo em Inglês | MEDLINE | ID: mdl-27382099

RESUMO

PURPOSE: WHO classification of myeloid malignancies is based mainly on the percentage of bone marrow (BM) blasts. This is considered from total nucleated cells (TNCs), unless there is erythroid-hyperplasia (erythroblasts ≥ 50%), calculated from nonerythroid cells (NECs). In these instances, when BM blasts are ≥ 20%, the disorder is classified as erythroleukemia, and when BM blasts are < 20%, as myelodysplastic syndrome (MDS). In the latter, the percentage of blasts is considered from TNCs. PATIENTS AND METHODS: We assessed the percentage of BM blasts from TNCs and NECs in 3,692 patients with MDS from the Grupo Español de Síndromes Mielodisplásicos, 465 patients with erythroid hyperplasia (MDS-E) and 3,227 patients without erythroid hyperplasia. We evaluated the relevance of both quantifications on classification and prognostication. RESULTS: By enumerating blasts systematically from NECs, 22% of patients with MDS-E and 12% with MDS from the whole series diagnosed within WHO categories with < 5% BM blasts, were reclassified into higher-risk categories and showed a poorer overall survival than did those who remained in initial categories (P = .006 and P = .001, respectively). Following WHO recommendations, refractory anemia with excess blasts (RAEB)-2 diagnosis is not possible in MDS-E, as patients with 10% to < 20% BM blasts from TNCs fulfill erythroleukemia criteria; however, by considering blasts from NECs, 72 patients were recoded as RAEB-2 and showed an inferior overall survival than did patients with RAEB-1 without erythroid hyperplasia. Recalculating the International Prognostic Scoring System by enumerating blasts from NECs in MDS-E and in the overall MDS population reclassified approximately 9% of lower-risk patients into higher-risk categories, which indicated the survival expected for higher-risk patients. CONCLUSION: Regardless of the presence of erythroid hyperplasia, calculating the percentage of BM blasts from NECs improves prognostic assessment of MDS. This fact should be considered in future WHO classification reviews.


Assuntos
Células da Medula Óssea/patologia , Síndromes Mielodisplásicas/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Eritroblastos/patologia , Feminino , Humanos , Leucemia Eritroblástica Aguda/diagnóstico , Leucemia Eritroblástica Aguda/patologia , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/diagnóstico , Prognóstico , Fatores de Risco , Espanha/epidemiologia , Adulto Jovem
13.
PLoS One ; 10(6): e0129375, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26066831

RESUMO

Isolated trisomy 8 is not considered presumptive evidence of myelodysplastic syndrome (MDS) in cases without minimal morphological criteria. One reason given is that trisomy 8 (+8) can be found as a constitutional mosaicism (cT8M). We tried to clarify the incidence of cT8M in myeloid neoplasms, specifically in MDS, and the diagnostic value of isolated +8 in MDS. Twenty-two MDS and 10 other myeloid neoplasms carrying +8 were studied. Trisomy 8 was determined in peripheral blood by conventional cytogenetics (CC) and on granulocytes, CD3+ lymphocytes and oral mucosa cells by fluorescence in situ hybridization (FISH). In peripheral blood CC, +8 was seen in 4/32 patients. By FISH, only one patient with chronic myelomonocytic leukemia showed +8 in all cell samples and was interpreted as a cT8M. In our series +8 was acquired in all MDS. Probably, once discarded cT8M by FISH from CD3+ lymphocytes and non-hematological cells, +8 should be considered with enough evidence to MDS.


Assuntos
Síndromes Mielodisplásicas/genética , Trissomia/genética , Estudos de Casos e Controles , Cromossomos Humanos Par 8/genética , Humanos
14.
Med. clín (Ed. impr.) ; 144(11): 487-490, jun. 2015. tab
Artigo em Espanhol | IBECS | ID: ibc-138027

RESUMO

Fundamento y objetivo: La leucemia mieloide crónica atípica (LMCa) y la leucemia neutrofílica crónica (LNC) presentan gran similitud clínico-analítica. El objetivo del estudio fue determinar el estado mutacional de SETBP1 y CSF3Ren dichas entidades. Pacientes y método: Se analizó el estado mutacional de SETBP1 y CSF3R en 7 pacientes con LMCa (n = 3), LNC (n = 1) y neoplasia mieloproliferativa (NMP) inclasificable (n = 3). Adicionalmente se estudiaron los genes ASXL1,SRSF2, IDH1/2, DNMT3A y RUNX1. Resultados: Se detectaron mutaciones en SETBP1 (G870S y G872R) en 2 pacientes con NMP inclasificable; uno de ellos presentó, además, mutaciones en SRSF2 (P95H) y ASXL1 (E635fs). El paciente afectado de LNC presentó mutaciones en CSFR3 (T618I), SETBP1 (G870S) y SRSF2 (P95H). Ningún paciente catalogado como LMCa mostró mutación de SETBP1 o CSF3R. De los pacientes con mutaciones, uno evolucionó a leucemia aguda mieloblástica y 2 presentaron progresión de la enfermedad sin llegar a documentarse transformación a leucemia. Conclusión: El conocimiento de las alteraciones moleculares involucradas en estas raras enfermedades es útil en el diagnóstico y podría tener repercusión tanto en el pronóstico como en el tratamiento (AU)


Background and objective: Atypical chronic myeloid leukemia (aCML) and chronic neutrophilic leukemia (CNL) display similar clinical and hematological characteristics. The objective of the present study was to determine the mutational status of SETBP1 and CSF3R in these diseases. Patients and method: The mutational status of SETBP1 and CSF3R was studied in 7 patients with aCML (n = 3), CNL (n = 1) and unclassifiable myeloproliferative neoplasms (MPN-u) (n = 3). Additionally, mutations in ASXL1,SRSF2, IDH1/2, DNMT3A, and RUNX1 were also analyzed. Results: SETBP1 mutations (G870S and G872R) were detected in 2 patients with MPN-u, and one of them also presented mutations in SRSF2 (P95H) and ASXL1 (E635fs). The CNL case showed mutations in CSFR3(T618I), SETBP1 (G870S) and SRSF2 (P95H). No patient classified as aCML had mutations in SETBP1or CSF3R. One of the patients with mutations evolved to acute myeloid leukemia, while the other 2 had disease progression without transformation to overt leukemia. Conclusion: The knowledge of the molecular alterations involved in these rare diseases is useful in the diagnosis and may have an impact on both prognosis and therapy (AU)


Assuntos
Leucemia Mieloide Crônica Atípica BCR-ABL Negativa/genética , Leucemia Neutrofílica Crônica/genética , Mutação/genética , Transtornos Mieloproliferativos/genética , Doenças Mieloproliferativas-Mielodisplásicas/genética
15.
Leuk Lymphoma ; 56(11): 3183-8, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25754580

RESUMO

Conventional G-banding cytogenetics (CC) detects chromosome 17 (chr17) abnormalities in 2% of patients with de novo myelodysplastic syndromes (MDS). We used CC and fluorescence in situ hybridization (FISH) (LSI p53/17p13.1) to assess deletion of 17p in 531 patients with de novo MDS from the Spanish Group of Hematological Cytogenetics. FISH detected - 17 or 17p abnormalities in 13 cases (2.6%) in whom no 17p abnormalities were revealed by CC: 0.9% of patients with a normal karyotype, 0% in non-informative cytogenetics, 50% of patients with a chr17 abnormality without loss of 17p and 4.7% of cases with an abnormal karyotype not involving chr17. Our results suggest that applying FISH of 17p13 to identify the number of copies of the TP53 gene could be beneficial in patients with a complex karyotype. We recommend using FISH of 17p13 in young patients with a normal karyotype or non-informative cytogenetics, and always in isolated del(17p).


Assuntos
Deleção Cromossômica , Cromossomos Humanos Par 17 , Hibridização in Situ Fluorescente , Síndromes Mielodisplásicas/genética , Proteína Supressora de Tumor p53/genética , Bandeamento Cromossômico , Humanos
17.
Med Clin (Barc) ; 144(11): 487-90, 2015 Jun 08.
Artigo em Espanhol | MEDLINE | ID: mdl-24854193

RESUMO

BACKGROUND AND OBJECTIVE: Atypical chronic myeloid leukemia (aCML) and chronic neutrophilic leukemia (CNL) display similar clinical and hematological characteristics. The objective of the present study was to determine the mutational status of SETBP1 and CSF3R in these diseases. PATIENTS AND METHOD: The mutational status of SETBP1 and CSF3R was studied in 7 patients with aCML (n = 3), CNL (n = 1) and unclassifiable myeloproliferative neoplasms (MPN-u) (n = 3). Additionally, mutations in ASXL1, SRSF2, IDH1/2, DNMT3A, and RUNX1 were also analyzed. RESULTS: SETBP1 mutations (G870S and G872R) were detected in 2 patients with MPN-u, and one of them also presented mutations in SRSF2 (P95H) and ASXL1 (E635fs). The CNL case showed mutations in CSFR3 (T618I), SETBP1 (G870S) and SRSF2 (P95H). No patient classified as aCML had mutations in SETBP1 or CSF3R. One of the patients with mutations evolved to acute myeloid leukemia, while the other 2 had disease progression without transformation to overt leukemia. CONCLUSION: The knowledge of the molecular alterations involved in these rare diseases is useful in the diagnosis and may have an impact on both prognosis and therapy.


Assuntos
Proteínas de Transporte/genética , Leucemia Mieloide Crônica Atípica BCR-ABL Negativa/genética , Leucemia Neutrofílica Crônica/genética , Mutação , Proteínas de Neoplasias/genética , Proteínas Nucleares/genética , Receptores de Fator Estimulador de Colônias/genética , Idoso , Idoso de 80 Anos ou mais , Subunidade alfa 2 de Fator de Ligação ao Core/genética , Análise Mutacional de DNA , DNA de Neoplasias/genética , Progressão da Doença , Evolução Fatal , Feminino , Humanos , Leucemia Mielomonocítica Aguda/genética , Masculino , Pessoa de Meia-Idade , Transtornos Mieloproliferativos/genética , Prognóstico , Proteínas Repressoras/genética , Ribonucleoproteínas/genética , Fatores de Processamento de Serina-Arginina
18.
Ann Hematol ; 93(10): 1695-703, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-24824767

RESUMO

Acute myeloid leukemia (AML) with myelodysplasia-related changes is characterized by the presence of multilineage dysplasia (MLD), frequently related to high-risk cytogenetics and poor outcome. However, the presence of MLD does not modify the favorable prognostic impact of NPM1 mutation. The prognosis of patients with AML presenting marked dysplasia lacking high-risk cytogenetics and NPM1 mutation is uncertain. We evaluated the prognostic impact of MLD in 177 patients with intermediate-risk cytogenetics AML (IR-AML) and wild-type NPM1. Patients were categorized as MLD-WHO (WHO myelodysplasia criteria; n = 43, 24 %), MLD-NRW (significant MLD non-reaching WHO criteria; n = 16, 9 %), absent MLD (n = 80, 45 %), or non-evaluable MLD (n = 38, 22 %). No differences concerning the main characteristics were observed between patients with or without MLD. Outcome of patients with MLD-WHO and MLD-NRW was similar, and significantly worse than patients lacking MLD. The presence of MLD (66 vs. 80 %, p = 0.03; HR, 95 % CI = 2.3, 1.08-4.08) and higher leukocyte count at diagnosis was the only variable associated with lower probability of complete remission after frontline therapy. Concerning survival, age and leukocytes showed an independent prognostic value, whereas MLD showed a trend to a negative impact (p = 0.087, HR, 95 % CI = 1.426, 0.95-2.142). Moreover, after excluding patients receiving an allogeneic stem cell transplantation in first CR, MLD was associated with a shorter survival (HR, 95 % CI = 1.599, 1.026-2.492; p = 0.038). In conclusion, MLD identifies a subgroup of patients with poorer outcome among patients with IR-AML and wild-type NPM1.


Assuntos
Medula Óssea/patologia , Linhagem da Célula , Leucemia Mieloide Aguda/patologia , Proteínas de Neoplasias/genética , Proteínas Nucleares/genética , Adolescente , Adulto , Idoso , Núcleo Celular/ultraestrutura , Citoplasma/ultraestrutura , Análise Mutacional de DNA , Feminino , Hematopoese , Humanos , Estimativa de Kaplan-Meier , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/mortalidade , Leucemia Mielomonocítica Aguda/tratamento farmacológico , Leucemia Mielomonocítica Aguda/genética , Leucemia Mielomonocítica Aguda/mortalidade , Leucemia Mielomonocítica Aguda/patologia , Contagem de Leucócitos , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/diagnóstico , Síndromes Mielodisplásicas/patologia , Prognóstico , Modelos de Riscos Proporcionais , Indução de Remissão , Risco , Adulto Jovem
19.
Clin Cancer Res ; 20(4): 1007-19, 2014 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-24352646

RESUMO

PURPOSE: According to current diagnostic criteria, mantle cell lymphoma (MCL) encompasses the usual, aggressive variants and rare, nonnodal cases with monoclonal asymptomatic lymphocytosis, cyclin D1-positive (MALD1). We aimed to understand the biology behind this clinical heterogeneity and to identify markers for adequate identification of MALD1 cases. EXPERIMENTAL DESIGN: We compared 17 typical MCL cases with a homogeneous group of 13 untreated MALD1 cases (median follow-up, 71 months). We conducted gene expression profiling with functional analysis in five MCL and five MALD1. Results were validated in 12 MCL and 8 MALD1 additional cases by quantitative reverse transcription polymerase chain reaction (qRT-PCR) and in 24 MCL and 13 MALD1 cases by flow cytometry. Classification and regression trees strategy was used to generate an algorithm based on CD38 and CD200 expression by flow cytometry. RESULTS: We found 171 differentially expressed genes with enrichment of neoplastic behavior and cell proliferation signatures in MCL. Conversely, MALD1 was enriched in gene sets related to immune activation and inflammatory responses. CD38 and CD200 were differentially expressed between MCL and MALD1 and confirmed by flow cytometry (median CD38, 89% vs. 14%; median CD200, 0% vs. 24%, respectively). Assessment of both proteins allowed classifying 85% (11 of 13) of MALD1 cases whereas 15% remained unclassified. SOX11 expression by qRT-PCR was significantly different between MCL and MALD1 groups but did not improve the classification. CONCLUSION: We show for the first time that MALD1, in contrast to MCL, is characterized by immune activation and driven by inflammatory cues. Assessment of CD38/CD200 by flow cytometry is useful to distinguish most cases of MALD1 from MCL in the clinical setting. MALD1 should be identified and segregated from the current MCL category to avoid overdiagnosis and unnecessary treatment.


Assuntos
Linfócitos B/fisiologia , Ciclina D1/metabolismo , Linfocitose/diagnóstico , Linfoma de Célula do Manto/diagnóstico , Doenças Assintomáticas , Estudos de Casos e Controles , Ciclina D1/genética , Diagnóstico Diferencial , Feminino , Citometria de Fluxo , Perfilação da Expressão Gênica , Humanos , Linfocitose/metabolismo , Linfoma de Célula do Manto/metabolismo , Linfoma de Célula do Manto/mortalidade , Masculino , Pessoa de Meia-Idade , Análise de Sobrevida , Transcriptoma
20.
Genes Chromosomes Cancer ; 52(12): 1167-77, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-24123380

RESUMO

Cytogenetic aberrations identified by metaphase cytogenetics (MC) have diagnostic, prognostic, and therapeutic implications in myelodysplastic syndromes (MDS). However, in some MDS patients MC study is unsuccesful. Single nucleotide polymorphism array (SNP-A) based karyotyping could be helpful in these cases. We performed SNP-A in 62 samples from bone marrow or peripheral blood of primary MDS with an unsuccessful MC study. SNP-A analysis enabled the detection of aberrations in 31 (50%) patients. We used the copy number alteration information to apply the International Prognostic Scoring System (IPSS) and we observed differences in survival between the low/intermediate-1 and intermediate-2/high risk patients. We also saw differences in survival between very low/low/intermediate and the high/very high patients when we applied the revised IPSS (IPSS-R). In conclusion, SNP-A can be used successfully in PB samples and the identification of CNA by SNP-A improve the diagnostic and prognostic evaluation of this group of MDS patients.


Assuntos
Cariotipagem/métodos , Síndromes Mielodisplásicas/diagnóstico , Polimorfismo de Nucleotídeo Único , Medula Óssea/patologia , Feminino , Dosagem de Genes , Humanos , Masculino , Síndromes Mielodisplásicas/genética , Análise de Sequência com Séries de Oligonucleotídeos/métodos , Prognóstico
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