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1.
Hematol Oncol ; 35(4): 778-788, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-27140599

RESUMO

Deoxyribonucleic acid microarrays allow researchers to measure mRNA levels of thousands of genes in a single experiment and could be useful for diagnostic purposes in patients with acute myeloid leukaemia (AML). We assessed the feasibility of the AML profiler (Skyline™ Array) in genetic stratification of patients with de novo AML and compared the results with those obtained using the standard cytogenetic and molecular approach. Diagnostic bone marrow from 31 consecutive de novo AML cases was used to test MLL-PTD, FLT3-ITD and TKD, NPM1 and CEBPAdm mutations. Purified RNA was used to assess RUNX1-RUNX1T1, PML-RARα and CBFß-MYH11 rearrangements. RNA remnants underwent gene expression profiling analysis using the AML profiler, which detects chromosomal aberrations: t(8;21), t(15;17), inv(16), mutations (CEBPAdm, ABD-NPM1) and BAALC and EVI1 expression. Thirty cases were successfully analysed with both methods. Five cases had FLT3-ITD. In one case, a t(8;21) was correctly detected by both methods. Four cases had inv(16); in one, the RNA quality was unsatisfactory and it was not hybridized, and in the other three, the AML profiler detected the genetic lesion - this being a rare type I translocation in one case. Two cases with acute promyelocytic leukaemia were diagnosed by both methods. Results for NPM1 mutations were concordant in all but two cases (2/11, non-ABD mutations). Analysis of costs and turnaround times showed that the AML profiler was no more expensive than the conventional molecular approach. These results suggest that the AML profiler could be useful in multicentre trials to rapidly identify patients with AML with a good prognosis. Copyright © 2016 John Wiley & Sons, Ltd.


Assuntos
Perfilação da Expressão Gênica/métodos , Leucemia Mieloide Aguda/genética , Estudos de Viabilidade , Feminino , Humanos , Leucemia Mieloide Aguda/patologia , Masculino , Prognóstico , Risco
2.
Hematol Oncol ; 34(2): 84-92, 2016 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25689772

RESUMO

The prognosis of chronic lymphocytic leukemia (CLL) patients displaying trisomy 12 (+12) remains unclear. In this study, we analyzed the influence of the proportion of cells with +12, and other clinical and biologic factors, in time to first therapy (TTFT) and overall survival (OS), in 289 patients diagnosed with CLL carrying +12. Median OS was 129 months. One hundred seventy-four patients (60.2%) presented +12 in <60% of cells. TTFT and OS for this subgroup were longer than for the subgroup with +12 in ≥60% of cells, with a median TTFT of 49 months (CI95%, 39-58) vs 30 months (CI95%, 22-38) (P = 0.001); and a median OS of 159 months (CI95%, 119-182), vs 96 months (CI95%, 58-134) (P = 0.015). Other factors associated with a shorter TTFT were: Binet stage, B symptoms, lymphadenopathy, splenomegaly, high lymphocyte count, 11q-, high ß2 microglobulin, and high LDH. In the multivariate analysis, clinical stage, +12 in ≥60% of cells, high lymphocyte count, B symptoms, and 11q- in addition, resulted of significance in predicting shorter TTFT. Significant variables for OS were: Binet stage, lymphadenopathy, splenomegaly, high LDH, high ß2 microglobulin, 11q-, and CD38. In the multivariate analysis, only Binet stage, 11q-, and high ß2microglobulin significantly predicted shorter OS. CLL with +12 entails a heterogeneous group with intermediate prognosis. However, a high proportion of cells carrying +12 separates a subgroup of patients with poor outcome. Copyright © 2015 John Wiley & Sons, Ltd.


Assuntos
Leucemia Linfocítica Crônica de Células B/genética , Leucemia Linfocítica Crônica de Células B/mortalidade , Trissomia/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Cromossomos Humanos Par 12/genética , Intervalo Livre de Doença , Feminino , Humanos , Leucemia Linfocítica Crônica de Células B/sangue , Leucemia Linfocítica Crônica de Células B/terapia , Masculino , Pessoa de Meia-Idade , Taxa de Sobrevida
3.
Am J Clin Pathol ; 144(3): 484-92, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26276779

RESUMO

OBJECTIVES: The prognostic impact of immunophenotypic markers in acute myeloid leukemia (AML) is controversial. METHODS: We retrospectively analyzed the value of CD34, CD117, CD7, and CD123 expression in a consecutive series of 592 adult patients with de novo AML. RESULTS: CD34+ measured as a percentage (≥2.88%) and CD34 mean fluorescence intensity (MFI) (≥146.79, arbitrary units [AU]) expression had a prognostic impact in terms of overall survival (OS; P = .005, P = .003), leukemia-free survival (LFS; P = .011, P < .001), and cumulative incidence of relapse (CIR; P = .014, P =. 001). The percentage of CD117+ cells (61.29%) was associated with shorter LFS (P =. 043), and CD117 MFI (≥284.01 AU) was associated with a shorter OS (P =. 033) and LFS (P =. 028). In the multivariate analysis, high CD34 MFI retained the independent value as predictor of LFS and CIR (P =. 012; hazard ratio [HR], 1.59; 95% confidence interval [CI], 1.11-2.28 and P =. 045; HR, 1.58; 95% CI, 1.01-2.46). CONCLUSIONS: CD34 positivity threshold with prognostic relevance is low (3% positive cells). Immunophenotypic findings in AML probably could only be fully exploited after a complex analysis that takes into account unconventional thresholds and the MFI.


Assuntos
Antígenos CD/análise , Leucemia Mieloide Aguda/diagnóstico , Adolescente , Adulto , Idoso , Antígenos CD/metabolismo , Biomarcadores/análise , Feminino , Citometria de Fluxo/métodos , Humanos , Imunofenotipagem , Leucemia Mieloide Aguda/metabolismo , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos
4.
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
5.
Br J Haematol ; 163(1): 47-54, 2013 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-23869550

RESUMO

Losses in 13q as a sole abnormality confer a good prognosis in chronic lymphocytic leukaemia (CLL). Nevertheless, its heterogeneity has been demonstrated and the clinical significance of biallelic 13q deletions remains controversial. We compared the clinico-biological characteristics of a series of 627 patients harbouring isolated 13q deletions by fluorescence in situ hybridization (FISH), either monoallelic (13q × 1), biallelic (13q × 2), or the coexistence of both clones (13qM). The most frequent 13q deletion was 13q × 1 (82·1%), while 13q × 2 and 13qM represented 8·6% and 9·3% of patients respectively. The median percentage of altered nuclei significantly differed across groups: 55%, 72·5% and 80% in 13q × 1, 13q × 2 and 13qM (P < 0·001). However, no significant differences in the clinical outcome among 13q groups were found. From 84 patients with sequential FISH studies, eight patients lost the remaining allele of 13q whereas none of them changed from 13q × 2 to the 13q × 1 group. The percentage of abnormal cells detected by FISH had a significant impact on the five-year cumulative incidence of treatment and the overall survival, 90% being the highest predictive power cut-off. In conclusion, loss of the remaining 13q allele is not enough to entail a worse prognosis in CLL. The presence of isolated 13q deletion can be risk-stratified according to the percentage of altered cells.


Assuntos
Alelos , Deleção Cromossômica , Cromossomos Humanos Par 13 , Leucemia Linfocítica Crônica de Células B/genética , Leucemia Linfocítica Crônica de Células B/mortalidade , Adulto , Idoso , Idoso de 80 Anos ou mais , Bandeamento Cromossômico , Feminino , Humanos , Hibridização in Situ Fluorescente , Leucemia Linfocítica Crônica de Células B/terapia , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Resultado do Tratamento
6.
Eur J Haematol ; 91(3): 209-18, 2013 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-23646898

RESUMO

PURPOSE: Most patients with acute myeloid leukemia (AML) and genetic rearrangements involving the core binding factor (CBF) have favorable prognosis. In contrast, a minority of them still have a high risk of leukemia recurrence. This study investigated the adverse features of CBF AML that could justify investigational therapeutic approaches. PATIENTS AND METHODS: One hundred and fifty patients (median age 42 yr, range 16-69) with CBF AML (RUNX1-RUNX1T1 n = 74; CBFB-MYH11 n = 76) were prospectively enrolled into two consecutive CETLAM protocols at 19 Spanish institutions. Main clinic and biologic parameters were analyzed in the whole series. In non-selected cases with available DNA samples, the impact of molecular characterization and minimal residual disease (MRD) was also studied. RESULTS: Overall, complete remission (CR) rate was 89% (94% in ≤50 yr old and 72% in >50 yr, P = 0.002). At 5 yr, cumulative incidence of relapse (CIR) was 26 ± 1%, disease-free survival (DFS) 62 ± 6%, and overall survival (OS) 66 ± 4%. In multivariate analyses, leukocyte count above 20 × 10(9) /L, BAALC over-expression, and high copy numbers of RUNX1-RUNXT1 or CBFB-MYH11 after induction chemotherapy (CT) led to increased relapse rate. Regarding OS, age >50 yr, leukocyte count above 20 × 10(9) /L, and increased MN1 expression were adverse features. CONCLUSION: Age, leukocyte counts, BAALC, and MN1 gene expressions as well as high copy numbers of RUNX1-RUNXT1 or CBFB-MYH11 after induction chemotherapy are useful tools to predict the outcome and should be considered for risk-adapted therapy.


Assuntos
Fatores de Ligação ao Core/genética , Leucemia Mieloide Aguda/genética , Adolescente , Adulto , Fatores Etários , Idoso , Subunidade alfa 2 de Fator de Ligação ao Core/genética , Feminino , Humanos , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/mortalidade , Contagem de Leucócitos , Masculino , Pessoa de Meia-Idade , Neoplasia Residual , Proteínas de Fusão Oncogênica/genética , Prognóstico , Proteína 1 Parceira de Translocação de RUNX1 , Recidiva , Translocação Genética , Adulto Jovem
7.
Hematol Oncol ; 31(2): 79-87, 2013 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-22961973

RESUMO

In this study, we described cytogenetics and fluorescence in situ hybridization (FISH) analysis performed in chronic lymphocytic leukaemia (CLL) patients with structural alterations. Results were correlated with clinical characteristics. A total of 38 CLL patients: 16 cases with complex and 22 with simple karyotypes were studied. For comparison of clinical parameters, a control group of 78 CLL patients with normal karyotype and without FISH genomic alterations were also evaluated. We found 38 structural abnormalities not previously described in the literature, 28 (74%) of them were translocations. In cases with complex karyotypes, chromosomes 6, 8 and 13 were the most frequently involved in new alterations (nine each), followed by chromosomes 12, 14 and 15 (six each). Chromosome 8p was particularly involved in losses, being 8p21-pter the commonest region of overlap. Cases with simple karyotypes, showed del(6q) as the most frequent alteration (39%). Del(9)(q11) was recurrent in our series. Analysis of clinical parameters showed significant differences in white blood count (p = 0.005) and platelet count (p = 0.015) between patients with structural alterations and the control group. In addition, patients with structural alterations had a significantly shorter time to first treatment (TFT) (29 months) than the control group (69 months) (p = 0.037). Cases with complex karyotypes had a lower proportion of patients in Rai 0 clinical stage (15.4% vs 75%) (p = 0.005) and higher ß2 microglobulin levels (3.3 vs 2.5 µg/mL) (p = 0.037) than those with simple karyotypes. Furthermore, a shorter TFT (13 months) and overall survival (56 months) in the complex karyotypes group compared with controls (69 and 144 months, respectively) (p = 0.015 and p = 0.005, respectively) were also found. Our results support the importance of cytogenetic analysis for clinical outcome in CLL and suggest that the diversity of genomic alterations is much greater than previously appreciated.


Assuntos
Leucemia Linfocítica Crônica de Células B/genética , Leucemia Linfocítica Crônica de Células B/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Análise Citogenética/métodos , Feminino , Humanos , Hibridização in Situ Fluorescente/métodos , Masculino , Pessoa de Meia-Idade
8.
Br J Haematol ; 157(1): 67-74, 2012 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-22224845

RESUMO

Patients with chronic lymphocytic leukaemia (CLL) whose tumour cells harbour a 17p deletion (17p-) are universally considered to have a poor prognosis. The deletion can be detected at diagnosis or during the evolution of the disease, particularly in patients who have received chemotherapy. We sought to evaluate the natural history of patients with 17p- CLL, identify predictive factors within this prognostic subgroup, and evaluate the results of different therapeutic approaches. Data from 294 patients with 17p- CLL followed up at 20 different institutions was retrospectively collected and analysed. Median age was 68 (range 27-98) years at the time of fluorescence in situ hybridization analysis. After 17p- documentation, 52% received treatment, achieving an overall response rate of 50%. Median overall survival was 41 months, and was significantly shorter in patients with elevated beta(2)-microglobulin concentration (P < 0·001), B symptoms (P = 0·016), higher percentage of cells with deletion (P < 0·001), and acquired deletions (P = 0·012). These findings suggest that patients with 17p- CLL have a variable prognosis that can be refined using simple clinical and laboratory features, including 17p- clone size, beta2-microglobulin concentration, presence of B symptoms and type of deletion (de novo versus acquired).


Assuntos
Deleção Cromossômica , Leucemia Linfocítica Crônica de Células B/mortalidade , Leucemia Linfocítica Crônica de Células B/terapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Cromossomos Humanos Par 17 , Intervalo Livre de Doença , Feminino , Seguimentos , Humanos , Hibridização in Situ Fluorescente , Leucemia Linfocítica Crônica de Células B/sangue , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Síndrome de Smith-Magenis , Taxa de Sobrevida , Microglobulina beta-2/sangue
9.
Hematol Oncol ; 30(3): 109-14, 2012 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-21812014

RESUMO

Acute promyelocytic leukaemia (APL) is a unique clinicobiologic entity that can be successfully treated with All-trans Retinoic Acid ATRA-based regimens. Some cases of acute myeloid leukaemia (AML) with nucleophosmin (NPM) mutations have an immunophenotype that is similar to APL. The objective of the study is to compare antigenic expression in a group of APL patients with that in AML patients with NPM mutations and an APL-like immunophenotype (CD15- CD34- HLA-DR-). A consecutive series of 40 APL and 12 NPM patients with an APL-like phenotype were included in the study. Immunophenotypic patterns were investigated by multiparametric flow cytometry. Promyelocytic leukaemia-retinoic acid receptor-α transcript type, NPM and FLT3 mutations were investigated using conventional methods. Statistically significant differences were found between APL and NPM-mutated AML in CD33, CD13, CD2 and CD110 reactivity. CD2 expression was absent in every patient with NPM-mutated AML. In addition, mean fluorescence intensity and the coefficient of variation (cv) of CD33 and CD13 showed statistical differences between the two groups for CD33 (p = 0.007) and a trend to significance for CD13 (p = 0.05). Furthermore, among 45 evaluable patients, CD110 expression statistically differentiates between the two groups: [2/33 (6%) in the APL group and 8/12 (66.6%) in the NPM-mutated AML (p = 0.014)]. However, these traits were subtle, raising the possibility of practical diagnostic challenges. In conclusion, CD110 and CD33 reactivity may be useful to distinguish APL from NPM-mutated AML with CD15, CD34 and HLA-DR negativity. Nevertheless, cytogenetic and molecular characterization is necessary to establish the accurate diagnosis of AML.


Assuntos
Antígenos CD/análise , Antígenos de Neoplasias/análise , Antígenos HLA-DR/análise , Imunofenotipagem , Leucemia Mieloide Aguda/diagnóstico , Leucemia Promielocítica Aguda/diagnóstico , Proteínas de Neoplasias/genética , Proteínas Nucleares/genética , Adulto , Antígenos CD34/análise , Diagnóstico Diferencial , Citometria de Fluxo , Fucosiltransferases/análise , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/imunologia , Leucemia Mieloide Aguda/patologia , Leucemia Promielocítica Aguda/genética , Leucemia Promielocítica Aguda/imunologia , Leucemia Promielocítica Aguda/patologia , Antígenos CD15/análise , Proteínas Proto-Oncogênicas c-bcr/genética , Receptores de Trombopoetina/análise , Tirosina Quinase 3 Semelhante a fms/genética
10.
PLoS One ; 5(9): e12855, 2010 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-20877721

RESUMO

BACKGROUND: NPM1 gene at chromosome 5q35 is involved in recurrent translocations in leukemia and lymphoma. It also undergoes mutations in 60% of adult acute myeloid leukemia (AML) cases with normal karyotype. The incidence and significance of NPM1 deletion in human leukemia have not been elucidated. METHODOLOGY AND PRINCIPAL FINDINGS: Bone marrow samples from 145 patients with myelodysplastic syndromes (MDS) and AML were included in this study. Cytogenetically 43 cases had isolated 5q-, 84 cases had 5q- plus other changes and 18 cases had complex karyotype without 5q deletion. FISH and direct sequencing investigated the NPM1 gene. NPM1 deletion was an uncommon event in the "5q- syndrome" but occurred in over 40% of cases with high risk MDS/AML with complex karyotypes and 5q loss. It originated from large 5q chromosome deletions. Simultaneous exon 12 mutations were never found. NPM1 gene status was related to the pattern of complex cytogenetic aberrations. NPM1 haploinsufficiency was significantly associated with monosomies (p<0.001) and gross chromosomal rearrangements, i.e., markers, rings, and double minutes (p<0.001), while NPM1 disomy was associated with structural changes (p=0.013). Interestingly, in complex karyotypes with 5q- TP53 deletion and/or mutations are not specifically associated with NPM1 deletion. CONCLUSIONS AND SIGNIFICANCE: NPM1/5q35 deletion is a consistent event in MDS/AML with a 5q-/-5 in complex karyotypes. NPM1 deletion and NPM1 exon 12 mutations appear to be mutually exclusive and are associated with two distinct cytogenetic subsets of MDS and AML.


Assuntos
Deleção de Genes , Leucemia Mieloide/genética , Proteínas Nucleares/genética , Translocação Genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Sequência de Bases , Criança , Deleção Cromossômica , Cromossomos Humanos Par 5/genética , Cromossomos Humanos Par 5/metabolismo , Feminino , Humanos , Leucemia Mieloide/metabolismo , Masculino , Pessoa de Meia-Idade , Dados de Sequência Molecular , Proteínas Nucleares/metabolismo , Adulto Jovem
11.
Genes Chromosomes Cancer ; 49(4): 327-32, 2010 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-20033916

RESUMO

Interphase fluorescence in situ hybridization (I-FISH) studies have a remarkable prognostic value in patients with chronic lymphocytic leukemia (CLL). I-FISH studies can be performed either on tetradecanoylphorbol acetate stimulated peripheral blood cells (I-FISH-TPA) or unstimulated peripheral blood mononuclear cells (I-FISH-PBMC). The aim of the study was to evaluate whether this finding was clinically relevant in a group of 235 patients with CLL. Fifty-six patients had both I-FISH-TPA and I-FISH-PBMC results. Compared with uncultured cells, the cytogenetic detection rate rose from 57 to 80% with the use of TPA-stimulated cells (P = 0.014). I-FISH-TPA provided a better prediction of treatment-free survival compared with I-FISH-PBMC (P = 0.031 vs. 0.166). Then, I-FISH-PBMC results from 93 historical patients were compared with 86 recent patients with I-FISH-TPA results. Genomic aberrations were detected in 46 and 67% of patients from the I-FISH-PBMC and I-FISH-TPA cohorts, respectively. The detection rate of 13q deletion as the only aberration increased from 10% with I-FISH-PBMC to 37% with I-FISH-TPA (P = 0.006). In conclusion, I-FISH-TPA increased the detection rate of 13q deletion and had an improved prognostic value compared with I-FISH-PBMC.


Assuntos
Hibridização in Situ Fluorescente/métodos , Leucemia Linfocítica Crônica de Células B/diagnóstico , Leucócitos Mononucleares/efeitos dos fármacos , Acetato de Tetradecanoilforbol/farmacologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Distribuição de Qui-Quadrado , Estudos de Coortes , Feminino , Humanos , Interfase/efeitos dos fármacos , Estimativa de Kaplan-Meier , Leucemia Linfocítica Crônica de Células B/sangue , Leucócitos Mononucleares/metabolismo , Leucócitos Mononucleares/patologia , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Prognóstico , Estimulação Química
12.
Haematologica ; 95(3): 424-31, 2010 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-19903674

RESUMO

BACKGROUND: Acute promyelocytic leukemia is a subtype of acute myeloid leukemia characterized by the t(15;17). The incidence and prognostic significance of additional chromosomal abnormalities in acute promyelocytic leukemia is still a controversial matter. DESIGN AND METHODS: Based on cytogenetic data available for 495 patients with acute promyelocytic leukemia enrolled in two consecutive PETHEMA trials (LPA96 and LPA99), we analyzed the incidence, characteristics, and outcome of patients with acute promyelocytic leukemia with and without additional chromosomal abnormalities who had been treated with all-trans retinoic acid plus anthracycline monochemotherapy for induction and consolidation. RESULTS: Additional chromosomal abnormalities were observed in 140 patients (28%). Trisomy 8 was the most frequent abnormality (36%), followed by abn(7q) (5%). Patients with additional chromosomal abnormalities more frequently had coagulopathy (P=0.03), lower platelet counts (P=0.02), and higher relapse-risk scores (P=0.02) than their counterparts without additional abnormalities. No significant association with FLT3/ITD or other clinicopathological characteristics was demonstrated. Patients with and without additional chromosomal abnormalities had similar complete remission rates (90% and 91%, respectively). Univariate analysis showed that additional chromosomal abnormalities were associated with a lower relapse-free survival in the LPA99 trial (P=0.04), but not in the LPA96 trial. However, neither additional chromosomal abnormalities overall nor any specific abnormality was identified as an independent risk factor for relapse in multivariate analysis. CONCLUSIONS: The lack of independent prognostic value of additional chromosomal abnormalities in acute promyelocytic leukemia does not support the use of alternative therapeutic strategies when such abnormalities are found.


Assuntos
Antineoplásicos/uso terapêutico , Aberrações Cromossômicas , Leucemia Promielocítica Aguda/tratamento farmacológico , Leucemia Promielocítica Aguda/genética , Tretinoína/uso terapêutico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Criança , Pré-Escolar , Cromossomos Humanos Par 15/genética , Cromossomos Humanos Par 17/genética , Estudos de Coortes , Feminino , Seguimentos , Humanos , Hibridização in Situ Fluorescente , Leucemia Promielocítica Aguda/patologia , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/patologia , Proteínas de Fusão Oncogênica/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Indução de Remissão , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Taxa de Sobrevida , Translocação Genética , Resultado do Tratamento , Adulto Jovem
13.
Leuk Res ; 33(12): 1643-9, 2009 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-19427034

RESUMO

Minimal residual disease may help to establish clinical decisions in patients with AML. WT1 offers the possibility to analyze those cases without currently known underlying genetic abnormalities. To compare the value of chimeric specific quantitative PCR with WT1 PCR in CBF acute leukemia, 445 samples from 96 AML (49 AML1-ETO+ and 47 CBFB-MYH11+) cases were included in the study. For each sample AML1-ETO or CBFB-MYH11 levels obtained using the conditions of the BIOMED group were compared with the results of WT1 levels using sensitive primers and conditions. Simultaneously, normal range expression of WT1 was established using RNA obtained from eight healthy donors. WT1 mutations were also investigated both at RNA and at the genomic level. The majority of CBF samples showed rises in WT1 levels (88.7%) at diagnosis. However, 18% of AML1-ETO showed WT1 levels below 250 copies in contrast with 5% CBFB-MYH11 cases. WT1 mutation was not detected in any case (70 diagnostic samples). We found correlation between WT1 levels at diagnosis and the CD34 blast population estimated by flow cytometry in CBFB-MYH11+ cases. We found no association between WT1 levels and clinical outcome. There was a high concordance between chimeric transcript analysis and WT1 levels in CR patients. Concordance was also high in relapsed patients (78% in AML1-ETO and 98% in CBFB-MYH11+ cases). Both WT1 and specific chimeric transcript identified and rescued false negative results of the other test. Additional studies are needed to determine whether the rare discrepancies are a reflection of the cooperative nature of WT1 overexpression or a consequence of the uneven distribution in the leukemic population. WT1 is a powerful MRD tool even in cases with currently available molecular targets.


Assuntos
Genes do Tumor de Wilms , Leucemia Mieloide Aguda/genética , Monitorização Fisiológica , Adolescente , Adulto , Idoso , Estudos de Casos e Controles , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , RNA/genética , Proteínas Recombinantes de Fusão/sangue , Adulto Jovem
14.
Br J Haematol ; 145(6): 801-5, 2009 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-19388937

RESUMO

Even in the era of newer and sophisticated prognostic markers, beta(2)-microglobulin (B2M) remains a simple but very powerful predictor of treatment-free survival (TFS) and overall survival (OS) in patients with chronic lymphocytic leukaemia (CLL). However, B2M levels are heavily influenced by the patient's glomerular filtration rate (GFR) and this study aimed to evaluate whether GFR-adjusted B2M (GFR-B2M) had improved prognostic value compared to unadjusted B2M in a cohort of over 450 consecutive CLL patients from two separate institutions. Multivariate analysis identified a significantly shorter TFS in patients who were ZAP-70 + (P < 0.001), with increased GFR-B2M (P < 0.001), and del(11q) or del(17p) as detected by fluorescence in situ hybridization (FISH; P < 0.001). When OS was evaluated by multivariate analysis, age 65 years or older (P < 0.001) and poor risk FISH abnormalities (P < 0.001) had a confirmed adverse prognostic impact, but the predictive value of GFR-B2M was lost in the validation analysis. In all survival models, B2M did not attain independent significance unless GFR-B2M was eliminated from the analysis. In conclusion, GFR-B2M is a better predictor of TFS than unadjusted B2M in CLL patients.


Assuntos
Biomarcadores Tumorais/sangue , Leucemia Linfocítica Crônica de Células B/sangue , Microglobulina beta-2/sangue , Adulto , Idoso , Idoso de 80 Anos ou mais , Creatinina/sangue , Feminino , Seguimentos , Taxa de Filtração Glomerular , Humanos , Leucemia Linfocítica Crônica de Células B/mortalidade , Masculino , Pessoa de Meia-Idade , Prognóstico , Modelos de Riscos Proporcionais , Curva ROC , Reprodutibilidade dos Testes , Taxa de Sobrevida
16.
Ann Hematol ; 87(10): 819-27, 2008 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-18587575

RESUMO

The CEBPA gene codes for a transcription factor that has a pivotal role in controlling proliferation and differentiation of myeloid progenitors. Acquired CEBPA mutations have been found in acute myeloid leukemias (AML) with a good prognosis, and most of these patients have a normal karyotype. In this paper, we report four cases that displayed the same K313dup in the CEBPA gene. All four had an AML-M1 with CD7 positivity and T-cell receptor gamma chain (TCR-gamma) rearrangement. This mutation could represent nearly 10% of all CEBPA mutations described to date. K313dup disappeared in samples from patients in complete remission. In transfected cells, the K313dup mutant had reduced protein stability with respect to the wild-type protein. K313dup seems to be selected in leukemic cells, and its frequency in other AML series could be determined using the screening method reported in this paper.


Assuntos
Proteínas Estimuladoras de Ligação a CCAAT/genética , Leucemia Mieloide Aguda/genética , Mutação , Adolescente , Adulto , Idoso , Proteínas Estimuladoras de Ligação a CCAAT/metabolismo , Análise Mutacional de DNA , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Receptores de Antígenos de Linfócitos T gama-delta/genética , Receptores de Antígenos de Linfócitos T gama-delta/metabolismo
17.
Leuk Lymphoma ; 49(6): 1178-83, 2008 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-18452069

RESUMO

The discovery of underlying genetic lesions helps to better understand the mechanisms of leukemogenesis and identify prognostic subgroups. Recent insights have allowed normal karyotype acute myeloid leukemia (AML) to be split into many molecular entities according to the genetic status of FLT3, NPM, CEBPA and MLL. Genome-wide single nucleotide polymorphism analysis was performed on 22 well-characterised AML patients with a normal karyotype. At the same time, microsatellite instability was investigated using a commonly used panel of polymorphic markers. Loss of heterozygosity (LOH) was found in 22.7% of cases without an associated copy number variation, suggesting that LOH represented an acquired partial uniparental disomy (aUPD) event. Three UPD+ cases harboured NPM mutations, associated with FLT3-ITD in two of them. An additional UPD patient had mutations both in CEBPA and in WT1. MSI was present at three loci in the three UPD+ cases (60%), whereas single locus MSI was present in three UPD- patients (17%). MSI involved the polymorphic PIG3 promoter in two UPD+ cases. It remains to be tested whether UPD and MSI association marks a common pathway of leukemogenesis.


Assuntos
Leucemia Mieloide Aguda/genética , Instabilidade de Microssatélites , Polimorfismo de Nucleotídeo Único/genética , Dissomia Uniparental/genética , Proteínas Estimuladoras de Ligação a CCAAT/genética , Dosagem de Genes , Rearranjo Gênico , Histona-Lisina N-Metiltransferase , Humanos , Cariotipagem , Leucemia Mieloide Aguda/patologia , Perda de Heterozigosidade , Análise em Microsséries , Mutação , Proteína de Leucina Linfoide-Mieloide/genética , Recidiva Local de Neoplasia/genética , Proteínas Nucleares/genética , Indução de Remissão , Proteínas WT1/genética , Tirosina Quinase 3 Semelhante a fms/genética
18.
Leuk Res ; 32(6): 944-53, 2008 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-18206229

RESUMO

Acute myeloid leukemia (AML) is a heterogeneous group of disorders characterized by an abnormal proliferation of the myeloid precursors and a maturation block. The most common chromosomal lesions in AML are the t(8;21) and inv(16). To better understand the leukemogenic mechanism of these fusion proteins, we performed gene expression studies in samples from (8;21), AML1 mutated and inv(16) patients, as well as from the Kasumi-1 cell line and a U937 cell line expressing the AML1-ETO fusion gene. To assess the influence of associated epigenetic lesions, we performed gene expression studies in Kasumi-1 cells and cells extracted from an Inv(16) patient, both treated with demethylating and HDAC inhibitor agents. Shared deregulated genes in the different types of core-binding factor leukemias were identified. We found a tight link between Inv(16) and mutant AML1 samples. Furthermore, some of the genes deregulated by the leukemogenic process reverted to their normal expression with demethylating and HDAC inhibitor treatment, highlighting the role of chromatin remodeling processes in AML.


Assuntos
Subunidade alfa 2 de Fator de Ligação ao Core/metabolismo , Metilação de DNA , Inibidores Enzimáticos/farmacologia , Epigênese Genética/efeitos dos fármacos , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Adulto , Azacitidina/análogos & derivados , Azacitidina/farmacologia , Biomarcadores Tumorais/genética , Montagem e Desmontagem da Cromatina , Inversão Cromossômica/genética , Cromossomos Humanos Par 16/genética , Cromossomos Humanos Par 21/genética , Cromossomos Humanos Par 8/genética , Subunidade alfa 2 de Fator de Ligação ao Core/genética , Metilases de Modificação do DNA/antagonistas & inibidores , Decitabina , Perfilação da Expressão Gênica , Regulação Leucêmica da Expressão Gênica/efeitos dos fármacos , Inibidores de Histona Desacetilases , Humanos , Ácidos Hidroxâmicos/farmacologia , Leucemia Mieloide Aguda/patologia , Mutação/genética , Análise de Sequência com Séries de Oligonucleotídeos , Proteínas de Fusão Oncogênica/genética , Regiões Promotoras Genéticas , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Proteína 1 Parceira de Translocação de RUNX1 , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Translocação Genética , Células Tumorais Cultivadas , Células U937
19.
Ann Hematol ; 87(3): 205-11, 2008 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-17909799

RESUMO

CEACAM family members are a set of widely expressed proteins involved in several biological functions, including cell adhesion, migration, signal transduction, and the regulation of gene expression. Abnormal overexpression and downregulation of some CEACAMs have been described in tumor cells. Monoclonal antibodies grouped in the CD66 cluster recognize CEACAM members. Ectopic CD66 expression is commonly detected in B-cell lineage acute lymphoblastic leukemia (ALL). To investigate the CEACAM messenger RNA (RNA) expression in leukemic blasts, we performed a quantitative polymerase chain reaction (RQ-PCR) analysis in purified RNA samples from a consecutive series of acute leukemias (135 patients). Most B-cell lineage ALL expressed CD66 (79.5%), whereas no single case of T-cell lineage ALL disclosed CD66 reactivity (0%). All the BCR-ABL+ ALL cases showed CD66 expression. CD66 was positive even in cases without CD10 expression (72.7%) and/or with MLL rearrangements. Despite the sharp contrast between T-ALL and B-ALL in CD66 reactivity, CEACAM patterns were comparable, and only minor differences for CEACAM1 and CEACAM8 were detected. All the leukemic samples showed overexpression of CEACAM6 and 8 when compared with normal granulocytes. These results were confirmed by dilutional experiments. The leukemic pattern paralleled the normal regenerating bone marrow with lower values for CEACAM1. In line with the results for CD66 reactivity, neoplastic cell lines had a uniform low expression of CEACAM family members. It remains to be investigated whether these CEACAM disturbances provide growth advantages to tumoral cells by inhibiting the anoikis process.


Assuntos
Antígenos CD/biossíntese , Crise Blástica/metabolismo , Moléculas de Adesão Celular/biossíntese , Regulação Leucêmica da Expressão Gênica , Proteínas de Neoplasias/biossíntese , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígenos CD/genética , Crise Blástica/genética , Adesão Celular/genética , Moléculas de Adesão Celular/genética , Movimento Celular/genética , Feminino , Proteínas Ligadas por GPI , Genes abl/genética , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas de Neoplasias/genética , Neprilisina/biossíntese , Neprilisina/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , RNA Neoplásico/biossíntese , RNA Neoplásico/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transdução de Sinais/genética
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