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1.
J Formos Med Assoc ; 116(10): 774-781, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28063722

RESUMO

BACKGROUND/PURPOSE: Real-time quantitative polymerase chain reaction (RQ-PCR) for fusion transcripts and flow cytometry for leukemia-specific markers are widely used for minimal residual disease (MRD) detection in acute lymphoblastic leukemia, but the relation between the results of either method is unclear. METHODS: Mononucleated cells from 108 bone marrow samples collected from 55 B-precursor acute lymphoblastic leukemia patients (30 with t(12;21)/ETV6-RUNX1, 16 with t(9;22)/BCR-ABL1 and nine with t(1;19)/TCF3-PBX1) were examined in tandem by RQ-PCR and six-color flow cytometry. RESULTS: MRD results were concordant in 91 of the 108 paired samples (84.2%; K=0.690); 49 samples were MRD-negative while 42 were MRD-positive by both methods, with < 1 log difference in positive MRD estimates in 39 samples (92.9%). Of the 17 discordant samples, 16 were MRD-positive by RQ-PCR but MRD-negative by flow cytometry; the opposite was true in one sample. Kappa value/concordance was 0.690/85.0% (n = 60) for ETV6-RUNX1, 0.842/93.3% (n = 15) for TCF3-PBX1, and 0.535/78.8% (n = 33) for BCR-ABL1. Specific immunophenotypic abnormalities were more prevalent in each genetic subgroup, such as CD38 underexpression, CD58 overexpression, and CD34 overexpression in ETV6-RUNX1, TCF3-PBX1, and BCR-ABL1, respectively. CONCLUSION: In most follow-up samples, MRD estimates by two methods are in agreement, especially in patients with TCF3-PBX1.


Assuntos
Neoplasia Residual/patologia , Proteínas de Fusão Oncogênica/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Doença Aguda , Medula Óssea/patologia , Citometria de Fluxo , Humanos , Imunofenotipagem , Reação em Cadeia da Polimerase , Análise de Regressão
2.
Haematologica ; 99(1): 28-36, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-23996483

RESUMO

Somatic mutations of TET2, IDH1, and IDH2 have been described in myelodysplastic syndrome. The impact of these mutations on outcome of myelodysplastic syndrome and their progression to secondary acute myeloid leukemia remains unclear. Mutation status of TET2, IDH1 and IDH2 was investigated in a cohort of 46 paired myelodysplastic syndrome/acute myeloid leukemia samples and 122 non-paired cases with de novo myelodysplastic syndrome, to clarify their roles in the evolution of myelodysplastic syndrome to acute myeloid leukemia. Among the 168 de novo myelodysplastic syndrome patients, the frequency of TET2, IDH1, and IDH2 mutations was 18.5%, 4.2% and 6.0%, respectively. TET2/IDH mutations had no impact on survivals, while TET2 mutations were significantly associated with rapid progression to acute myeloid leukemia. Seventeen of the 46 paired myelodysplastic syndrome/secondary acute myeloid leukemia samples harbored TET2/IDH mutations; none acquired these mutations in acute myeloid leukemia phase. Progression to acute myeloid leukemia was accompanied by evolution of a novel clone or expansion of a minor pre-existing subclone of one or more distinct mutations in 12 of the 17 cases with TET2/IDH mutations. A minor subclone in 3 cases with biallelic TET2 inactivation subsequently expanded, indicating biallelic TET2 mutations play a role in acute myeloid leukemia progression. Twelve patients acquired other genetic lesions, and/or showed increased relative mutant allelic burden of FLT3-ITD, N/K-RAS, CEBPA or RUNX1 during acute myeloid leukemia progression. Our findings provide a novel insight into the role of TET2/IDH mutation in the pathogenesis of myelodysplastic syndrome and subsequent progression to acute myeloid leukemia.


Assuntos
Transformação Celular Neoplásica/genética , Proteínas de Ligação a DNA/genética , Isocitrato Desidrogenase/genética , Mutação , Síndromes Mielodisplásicas/genética , Síndromes Mielodisplásicas/patologia , Proteínas Proto-Oncogênicas/genética , Idoso , Idoso de 80 Anos ou mais , Medula Óssea/patologia , Células Clonais , Dioxigenases , Progressão da Doença , Feminino , Dosagem de Genes , Frequência do Gene , Humanos , Cariótipo , Leucemia/genética , Leucemia/patologia , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/mortalidade , Polimorfismo de Nucleotídeo Único
3.
Leuk Res ; 37(1): 43-9, 2013 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-23062378

RESUMO

Some chronic myeloid leukemia (CML) patients treated with tyrosine kinase inhibitor (TKI) do not respond or relapse. BCR-ABL1 mutations are the principal cause of TKI resistance, but the kinetics of emerging mutations in CML patients treated with imatinib remain to be determined. To investigate the emergence dynamics of mutations and their effects on outcomes, we conducted a systematically longitudinal study of BCR-ABL1 mutation dynamics during TKI therapy. Seminested polymerase chain reaction followed by denaturing high-performance liquid chromatography with sequence confirmation were used to detect BCR-ABL1 mutations in 202 CML patients with imatinib resistance at different CML phases. We detected 68 mutations in 58 imatinib-failure patients. Mutations were present in 27.6% of patients who failed front-line imatinib therapy and in 68.1% with advanced disease. Mutations were not detected in patients before commencing imatinib treatment. Pyrosequencing was then used to quantitatively monitor the mutant levels sequentially and also traced back for their earlier appearance. The mutants differed in rapidity of emergence which appeared to arise in different time frame as well as in speed of rising mutant levels. In the 78 front-line imatinib-failure patients, mutation positive patients had significantly higher risk of disease progression or relapse and inferior progression-free survival compared to those without mutations (p=0.006). Our study demonstrates kinetics of different BCR-ABL1 mutant emergence and an association between BCR-ABL1 mutations and disease progression.


Assuntos
Antineoplásicos/uso terapêutico , Proteínas de Fusão bcr-abl/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Mutação , Piperazinas/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Tirosina Quinases/antagonistas & inibidores , Pirimidinas/uso terapêutico , Benzamidas , Feminino , Humanos , Mesilato de Imatinib , Pessoa de Meia-Idade , Falha de Tratamento
4.
Neoplasia ; 13(11): 1035-42, 2011 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-22131879

RESUMO

The molecular pathogenesis of myelodysplastic syndrome (MDS) and its progression to secondary acute myeloid leukemia (sAML) remain to be explored. Somatic C-CBL mutations were recently described in MDS. Our study aimed to determine the role of C-CBL mutations in the progression of MDS to sAML and sought to correlate with clinicohematological features and outcome. Bone marrow samples from 51 patients with high-risk MDS (13 with refractory cytopenia with multilineage dysplasia, 19 with refractory anemia with excess blast 1, and 19 with refractory anemia with excess blast 2) were analyzed for C-CBL mutations at both diagnosis and sAML in the same individuals. Mutational analysis was performed for exons 7 to 9 of C-CBL gene. Of the 51 paired samples, C-CBL mutations were identified in 6 patients at the sAML phase. One patient retained the identical C-CBL mutation (G415S) at sAML evolution and exhibited clonal expansion. The other five patients acquired C-CBL mutations (Y371S, F418S, L370_Y371 ins L, L399V, and C416W) during sAML evolution. Three of the six patients harboring C-CBL mutations at sAML had additional gene mutations including JAK2(V617F), PTPN11, or N-RAS. There was no significant difference in clinicohematological features and overall survival with respect to C-CBL mutation status. Our results show that C-CBL mutation is very rare (0.6%) in MDS, but acquisition and/or expansion of C-CBL mutant clones occur in 11.8% of patients during sAML transformation. The findings suggest that C-CBL mutations play a role at least in part in a subset of MDS patients during sAML transformation.


Assuntos
Proliferação de Células , Leucemia Mieloide Aguda/genética , Síndromes Mielodisplásicas/genética , Proteínas Proto-Oncogênicas c-cbl/genética , Adulto , Idoso , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/patologia , Células Clonais/metabolismo , Células Clonais/patologia , Células Clonais/fisiologia , Estudos de Coortes , Progressão da Doença , Feminino , Frequência do Gene , Humanos , Leucemia Mieloide Aguda/patologia , Masculino , Pessoa de Meia-Idade , Mutação , Síndromes Mielodisplásicas/patologia , Risco , Adulto Jovem
5.
Blood ; 100(5): 1596-601, 2002 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-12176877

RESUMO

Essential thrombocythemia (ET) is a heterogeneous disorder in which the clonality of hematopoiesis varies. The clinical significance of clonality status in ET remains to be determined. We used the human androgen receptor gene (HUMARA)-polymerase chain reaction assay to investigate X-chromosome inactivation patterns (XCIPs) and their value in predicting vascular complications in 89 female patients with ET. Fifty-four (68.4%) patients had a clonal pattern of XCIP, and 15 (19.0%) had a polyclonal pattern. The remaining 20 patients had either an ambiguous or a homozygous pattern of XCIP and were therefore excluded from further analysis. Patients with clonal XCIPs were older (P =.029) and were at greater risk for thrombosis (P =.007) than were those with polyclonal XCIPs. We did not find a correlation between the occurrence of hemorrhage and XCIP (P =.492). Advanced age was predictive of thrombosis and hemorrhage. Platelet count did not influence the risk for vascular complications. Hypertension was significantly correlated with thrombotic events (P =.002), whereas diabetes mellitus and hypercholesterolemia were of no predictive value. In a multivariate analysis, age was the significant predictor of thrombosis (P =.030); however, XCIPs (P =.083) and hypertension (P =.073) tended to predict thrombosis. Our results suggest that older patients who have clonal XCIPs or hypertension are at increased risk for thrombosis and should be monitored closely for this complication.


Assuntos
Mecanismo Genético de Compensação de Dose , Trombocitose/complicações , Trombocitose/genética , Trombose/etiologia , Adulto , Idoso , Feminino , Seguimentos , Hemorragia/etiologia , Hemorragia/genética , Humanos , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase , Valor Preditivo dos Testes , Fatores de Risco , Trombose/genética
6.
Cancer ; 98(6): 1206-16, 2003 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-12973844

RESUMO

BACKGROUND: The clinical relevance of mutations of the FMS-like tyrosine kinase 3 (FLT3) gene in specific cytogenetic subgroups is not clear. The authors examined internal tandem duplication (ITD) and Asp835 mutations of FLT3 in patients with acute promyelocytic leukemia (APL) to determine the incidence of these mutations and to analyze the results for correlations with clinicohematologic features and outcome. METHODS: Bone marrow samples from 107 patients with APL were analyzed. Isoforms of PML-RAR alpha were identified using a reverse transcription-polymerase chain reaction assay. A standard polymerase chain reaction (PCR) assay was used to detect FLT3/ITD mutations. Asp835 mutations were analyzed by PCR amplification of exon 20 followed by EcoRV digestion. All aberrant PCR products subsequently were sequenced. RESULTS: Twenty-two patients had FLT3/ITD mutations: 9 of 63 patients with L-type PML/RAR alpha, 13 of 34 patients with S-type PML/RAR alpha, and 0 of 10 patients with V-type PML/RAR alpha (P = 0.005). The incidence of FLT3/ITD mutations was significantly higher in patients with S-type PML/RAR alpha than in patients with L-type PML/RAR alpha or V-type PML/RAR alpha. Twenty patients had Asp835 mutations (L-type PML/RAR alpha: n = 11; S-type PML/RAR alpha: n = 8; V-type PML/RAR alpha: n = 1). The frequency of Asp835 mutations was not significantly different among patients with different PML/RAR alpha isoforms (P = 0.582). Three patients had both ITD and Asp835 mutations. The microgranular variant (M3v) form of leukemia was found to be associated with a higher frequency of ITD (P = 0.002) but not with a higher frequency of Asp835 mutations (P = 1.000); analysis of clinicohematologic variables revealed no significant differences in FLT3 mutation incidence among other patient subgroups. There was no significant difference in complete remission rate, overall survival, or event-free survival between patients with ITDs and those without ITDs or between patients with Asp835 mutations and those without Asp835 mutations. CONCLUSIONS: The current study found that ITD or Asp835 mutations of the FLT3 gene were present in 36.4% of patients with APL; however, these mutations had no prognostic impact. FLT3/ITD frequently was associated with S-type PML/RAR alpha and with the M3v form of leukemia.


Assuntos
Duplicação Gênica , Leucemia Promielocítica Aguda/genética , Mutação , Proteínas Proto-Oncogênicas/genética , Receptores Proteína Tirosina Quinases/genética , Adulto , Ácido Aspártico/genética , Criança , Feminino , Humanos , Leucemia Promielocítica Aguda/mortalidade , Leucemia Promielocítica Aguda/patologia , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase , Recidiva , Resultado do Tratamento , Tirosina Quinase 3 Semelhante a fms
7.
Blood ; 100(7): 2387-92, 2002 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-12239146

RESUMO

Analysis of internal tandem duplications of FLT3 (FLT3/ITD) was performed on bone marrow samples obtained at diagnosis and relapse from 108 adult patients with de novo acute myeloid leukemia (AML) to determine the role of this mutation in leukemic relapse. Eighty-three patients had wild-type FLT3 at both diagnosis and relapse, 16 had FLT3/ITD at both stages, whereas 8 had acquired the mutation and 1 had lost it at relapse. Using Genescan analysis, we found that FLT3/ITD levels at first relapse were significantly higher than those at diagnosis (mean +/- SE, 40.5% +/- 4.8% versus 17.9% +/- 3.6%, P <.001). The increase in mutation levels at relapse as compared with diagnosis did not correlate with the difference in blast cell percentages at both stages (P =.777). A hemizygous deletion of wild-type FLT3 was found in 4 patients at relapse compared to none at diagnosis. Nine of the 11 patients carrying a single mutation at diagnosis relapsed with an identical mutation. All 6 patients with more than one FLT3/ITD mutation at diagnosis showed changes in mutation patterns and levels at first relapse; however, each patient retained at least one mutation in the relapse sample. The changes of mutation patterns had implications for the monitoring of minimal residual disease. Our results suggest that FLT3/ITD may contribute as the initial transforming event in AML, and relapse can reflect the selection and outgrowth of a mutant clone or evolution of a new clone harboring this mutation.


Assuntos
Medula Óssea/patologia , Duplicação Gênica , Leucemia Mieloide Aguda/genética , Proteínas Proto-Oncogênicas/genética , Receptores Proteína Tirosina Quinases/genética , Adulto , Crise Blástica/genética , Aberrações Cromossômicas , Feminino , Humanos , Leucemia Mieloide Aguda/patologia , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase , Recidiva , Estudos Retrospectivos , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Tirosina Quinase 3 Semelhante a fms
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