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1.
Eur J Haematol ; 100(2): 154-162, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29114972

RESUMO

OBJECTIVES: Randomized comparison of two treatment strategies in frontline therapy of acute promyelocytic leukemia (APL): all-trans retinoic acid (ATRA) and double induction intensified by high-dose cytosine arabinoside (HD ara-C) (German AMLCG) and therapy with ATRA and anthracyclines (Spanish PETHEMA, LPA99). PATIENTS AND RESULTS: Eighty of 87 adult patients with genetically confirmed APL of all risk groups were eligible. The outcome of both arms was similar: AMLCG vs PETHEMA: hematological complete remission 87% vs 83%, early death 13% vs 17% (P = .76), overall survival, event-free survival, leukemia-free survival, cumulative incidence of relapse at 6 years 75% vs 78% (P = .92); 75% vs 68% (P = .29); 86% vs 81% (P = .28); and 0% vs 12% (P = .04, no relapse vs four relapses), respectively. The median time to achieve molecular remission (RT-PCR negativity of PML-RARA) was 60 days in both arms (P = .12). The AMLCG regimen was associated with a longer duration of neutropenia (P = .02) and a higher rate of WHO grade ≥3 infections. CONCLUSIONS: The small number of patients limits the reliability of conclusions. With these restrictions, the outcomes of both approaches were similar and show the limitations of ATRA and chemotherapy. The HD ara-C-containing regimen was associated with a lower relapse rate in high-risk APL.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Leucemia Promielocítica Aguda/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antraciclinas/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Biomarcadores , Quimioterapia de Consolidação , Citarabina/administração & dosagem , Análise Citogenética , Feminino , Humanos , Leucemia Promielocítica Aguda/diagnóstico , Leucemia Promielocítica Aguda/mortalidade , Masculino , Pessoa de Meia-Idade , Neoplasia Residual/patologia , Recidiva , Indução de Remissão , Análise de Sobrevida , Resultado do Tratamento , Tretinoína/administração & dosagem , Adulto Jovem
2.
Blood ; 125(19): 2985-94, 2015 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-25805812

RESUMO

The gene CXXC5 on 5q31 is frequently deleted in acute myeloid leukemia (AML) with del(5q), suggesting that inactivation of CXXC5 might play a role in leukemogenesis. Here, we investigated the functional and prognostic implications of CXXC5 expression in AML. CXXC5 mRNA was downregulated in AML with MLL rearrangements, t(8;21) and GATA2 mutations. As a mechanism of CXXC5 inactivation, we found evidence for epigenetic silencing by promoter methylation. Patients with CXXC5 expression below the median level had a lower relapse rate (45% vs 59%; P = .007) and a better overall survival (OS, 46% vs 28%; P < .001) and event-free survival (EFS, 36% vs 21%; P < .001) at 5 years, independent of cytogenetic risk groups and known molecular risk factors. In gene-expression profiling, lower CXXC5 expression was associated with upregulation of cell-cycling genes and co-downregulation of genes implicated in leukemogenesis (WT1, GATA2, MLL, DNMT3B, RUNX1). Functional analyses demonstrated CXXC5 to inhibit leukemic cell proliferation and Wnt signaling and to affect the p53-dependent DNA damage response. In conclusion, our data suggest a tumor suppressor function of CXXC5 in AML. Inactivation of CXXC5 is associated with different leukemic pathways and defines an AML subgroup with better outcome.


Assuntos
Proteínas de Transporte/genética , Regulação Leucêmica da Expressão Gênica , Leucemia Mieloide Aguda/genética , Mutação/genética , Proteínas Wnt/antagonistas & inibidores , Adolescente , Adulto , Idoso , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Proteínas de Transporte/antagonistas & inibidores , Proteínas de Transporte/metabolismo , Ciclo Celular , Estudos de Coortes , Metilação de DNA , Proteínas de Ligação a DNA , Regulação para Baixo , Feminino , Seguimentos , Perfilação da Expressão Gênica , Humanos , Técnicas Imunoenzimáticas , Leucemia Mieloide Aguda/mortalidade , Leucemia Mieloide Aguda/patologia , Masculino , Pessoa de Meia-Idade , Análise de Sequência com Séries de Oligonucleotídeos , Prognóstico , Regiões Promotoras Genéticas/genética , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transdução de Sinais , Taxa de Sobrevida , Fatores de Transcrição , Células Tumorais Cultivadas , Adulto Jovem
3.
Genes Chromosomes Cancer ; 55(1): 82-94, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26493028

RESUMO

T-cell prolymphocytic leukemia (T-PLL) is a rare post-thymic T-cell neoplasm with aggressive clinical course and short overall survival. So far, due to the rareness of this disease, genetic data are available only from individual cases or small cohorts. In our study, we aimed at performing a comprehensive cytogenetic and molecular genetic characterization of T-PLL comprising the largest cohort of patients with T-PLL analyzed so far, including correlations between the respective markers and their impact on prognosis. Genetic abnormalities were found in all 51 cases with T-PLL, most frequently involving the TCRA/D locus (86%). Deletions were detected for ATM (69%) and TP53 (31%), whereas i(8)(q10) was observed in 61% of cases. Mutations in ATM, TP53, JAK1, and JAK3 were detected in 73, 14, 6, and 21% of patients, respectively. Additionally, BCOR mutations were observed for the first time in a lymphoid malignancy (8%). Two distinct genetic subgroups of T-PLL were identified: A large subset (86% of patients) showed abnormalities involving the TCRA/D locus activating the proto-oncogenes TCL1 or MTCP1, while the second group was characterized by a high frequency of TP53 mutations (4/7 cases). Further, analyses of overall survival identified JAK3 mutations as important prognostic marker, showing a significant negative impact.


Assuntos
Janus Quinase 3/genética , Leucemia Prolinfocítica de Células T/genética , Leucemia Prolinfocítica de Células T/patologia , Mutação , Adulto , Idoso , Idoso de 80 Anos ou mais , Aberrações Cromossômicas , Feminino , Variação Genética , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Análise de Sequência de DNA , Análise de Sobrevida
4.
Genes Chromosomes Cancer ; 55(2): 148-57, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26542308

RESUMO

In acute myeloid leukemia (AML), acquired genomic gains and losses are common and lead to altered expression of genes located within or nearby the affected regions. Increased expression of the ETS-related transcription factor gene ERG has been described in myeloid malignancies with chromosomal rearrangements involving chromosome band 21q22, but also in cytogenetically normal AML, where it is associated with adverse prognosis. In this study, fluorescence in situ hybridization on interphase nuclei disclosed an amplification of the ERG gene (more than six copies) in 33 AML patients with structural rearrangements of 21q22. Array comparative genomic hybridization of these cases disclosed a minimal amplified region at the position 39.6-40.0 Mbp from pter that harbors ERG as the only gene. Analysis by quantitative real-time reverse transcription polymerase chain reaction revealed significantly higher ERG mRNA expression in these patients and in a group of 95 AML patients with complete or partial gain of chromosome 21 (three to six copies) compared with 351 AML patients without gain of chromosome 21. Quantification of ERG DNA copy numbers revealed a strong correlation with ERG mRNA expression. Furthermore, in patients with gain of chromosome 21, higher ERG expression was found to be associated with RUNX1 mutations. Our results suggest that acquired gain of chromosome 21 or amplification of chromosome arm 21q is one mechanism contributing to increased ERG expression in AML.


Assuntos
Cromossomos Humanos Par 21/genética , Amplificação de Genes , Regulação Neoplásica da Expressão Gênica , Leucemia Mieloide Aguda/genética , Transativadores/genética , Idoso , Idoso de 80 Anos ou mais , Duplicação Cromossômica , Hibridização Genômica Comparativa , Subunidade alfa 2 de Fator de Ligação ao Core/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Regulador Transcricional ERG
5.
Br J Haematol ; 175(5): 904-916, 2016 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-27662611

RESUMO

High BAALC gene expression has been associated with poor prognosis in cytogenetically normal acute myeloid leukaemia (CN-AML) and has been suggested as a suitable marker for assessing minimal residual disease (MRD). The purpose of this study was to substantiate these findings by the analysis of a large data set of 632 diagnostic and follow-up samples in 142 intensively treated CN-AML patients. Paired diagnostic/relapse samples of 35 patients revealed stable high BAALC expression in 89%, irrespective of a high proportion of clonal evolution found in 49% of these cases. High BAALC expression, both directly after induction chemotherapy and within 3-6 months after induction chemotherapy, correlated significantly with shorter event-free survival and overall survival. Moreover, 8 of 10 patients displaying high BAALC expression levels after completion of induction therapy as well as 5 of 5 patients exhibiting high BAALC expression levels within 3-6 months after induction chemotherapy experienced relapse with a median of 197 and 101 days, respectively, from sampling to relapse. Thus, BAALC expression-based MRD detection during therapy may be considered a strategy to identify patients at high risk of relapse.


Assuntos
Leucemia Mieloide Aguda/diagnóstico , Proteínas de Neoplasias/genética , Neoplasia Residual/diagnóstico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Intervalo Livre de Doença , Estudos de Viabilidade , Feminino , Expressão Gênica , Humanos , Cariótipo , Leucemia Mieloide Aguda/mortalidade , Masculino , Pessoa de Meia-Idade , Recidiva , Indução de Remissão , Medição de Risco/métodos , Taxa de Sobrevida , Adulto Jovem
6.
Blood ; 124(2): 251-8, 2014 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-24829203

RESUMO

TP53 is the most extensively studied gene in cancer. However, data on frequency and the prognostic impact of TP53 mutations in acute lymphoblastic leukemia (ALL) remain scarce. Thus, we aimed at identifying the mutation frequency of TP53, its association with cytogenetic subgroups, and its impact on survival in a large cohort of 625 patients with ALL. Our data revealed an overall mutation incidence of 15.7%, which increases with age. Correlation with cytogenetic subgroups showed that mutations were most frequent in ALL with low hypodiploidy or MYC-rearrangements. Furthermore, for a large number of patients, both TP53 alleles were altered, either by 2 TP53 mutations (12%) or by a TP53 mutation and a TP53 deletion in the second allele (39%). A high TP53 mutation load was correlated to low hypodiploidy, high hyperdiploidy, and a complex karyotype. Moreover, a higher mutation load was found in B-lineage ALL compared with T-lineage ALL. Similar to other cancers, the median overall survival was significantly shorter in patients with TP53 mutation compared with patients with wild-type TP53. This effect was especially pronounced when both TP53 alleles were affected, either by 2 TP53 mutations or by both a mutation and an accompanying TP53 deletion.


Assuntos
Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidade , Proteína Supressora de Tumor p53/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Feminino , Frequência do Gene , Genes myc/genética , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Mutação , Ploidias , Prognóstico , Translocação Genética , Adulto Jovem
7.
Blood ; 123(12): 1883-6, 2014 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-24493670

RESUMO

We describe the development of acute myeloid leukemia (AML) in an adult with CBL syndrome caused by a heterozygous de novo germline mutation in CBL codon D390. In the AML bone marrow, the mutated CBL allele was homozygous after copy number-neutral loss-of-heterozygosity and amplified through a chromosomal gain; moreover, an inv(16)(p13q22) and, as assessed by whole-exome sequencing, 12 gene mutations (eg, in CAND1, NID2, PTPRT, DOCK6) were additionally acquired. During complete remission of the AML, in the presence of normal blood counts, the hematopoiesis stably maintained the homozygous CBL mutation, which is reminiscent of the situation in children with CBL syndrome and transient juvenile myelomonocytic leukemia. No additional mutations were identified by whole-exome sequencing in granulocytes during complete remission. The study highlights the development of AML in an adult with CBL syndrome and, more generally, in genetically aberrant but clinically inconspicuous hematopoiesis.


Assuntos
Leucemia Mieloide Aguda/genética , Proteínas Proto-Oncogênicas c-cbl/genética , Adulto , Aberrações Cromossômicas , Cromossomos Humanos Par 11/genética , Amplificação de Genes , Mutação em Linhagem Germinativa , Doenças Hematológicas/complicações , Doenças Hematológicas/genética , Hematopoese/genética , Homozigoto , Humanos , Leucemia Mieloide Aguda/etiologia , Perda de Heterozigosidade , Masculino , Esferocitose Hereditária/complicações , Esferocitose Hereditária/genética , Síndrome
8.
Blood ; 123(14): 2229-37, 2014 Apr 03.
Artigo em Inglês | MEDLINE | ID: mdl-24523240

RESUMO

Severe congenital neutropenia (CN) is a preleukemic bone marrow failure syndrome with a 20% risk of evolving into leukemia or myelodysplastic syndrome (MDS). Patterns of acquisition of leukemia-associated mutations were investigated using next-generation deep-sequencing in 31 CN patients who developed leukemia or MDS. Twenty (64.5%) of the 31 patients had mutations in RUNX1. A majority of patients with RUNX1 mutations (80.5%) also had acquired CSF3R mutations. In contrast to their high frequency in CN patients who developed leukemia or MDS, RUNX1 mutations were found in only 9 of 307 (2.9%) patients with de novo pediatric acute myeloid leukemia. A sequential analysis at stages prior to overt leukemia revealed RUNX1 mutations to be late events in leukemic transformation. Single-cell analyses in 2 patients showed that RUNX1 and CSF3R mutations were present in the same malignant clone. Functional studies demonstrated elevated granulocyte colony-stimulating factor (G-CSF)-induced proliferation with diminished myeloid differentiation of hematopoietic CD34(+) cells coexpressing mutated forms of RUNX1 and CSF3R. The high frequency of cooperating RUNX1 and CSF3R mutations in CN patients suggests a novel molecular pathway of leukemogenesis: mutations in the hematopoietic cytokine receptor (G-CSFR) in combination with the second mutations in the downstream hematopoietic transcription fator (RUNX1). The detection of both RUNX1 and CSF3R mutations could be used as a marker for identifying CN patients with a high risk of progressing to leukemia or MDS.


Assuntos
Transformação Celular Neoplásica/genética , Subunidade alfa 2 de Fator de Ligação ao Core/genética , Leucemia Mieloide/genética , Mutação , Neutropenia/congênito , Receptores de Fator Estimulador de Colônias/genética , Adolescente , Adulto , Criança , Pré-Escolar , Síndrome Congênita de Insuficiência da Medula Óssea , Análise Citogenética , Feminino , Humanos , Masculino , Neutropenia/genética , Neutropenia/patologia , Transdução de Sinais/genética , Adulto Jovem
9.
Genes Chromosomes Cancer ; 54(12): 762-70, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26355392

RESUMO

In eosinophilia-associated myeloproliferative neoplasms (MPN-eo), constitutive activation of protein tyrosine kinases (TK) as consequence of translocations, inversions, or insertions and creation of TK fusion genes is recurrently observed. The most commonly involved TK and their potential TK inhibitors include PDGFRA at 4q12 or PDGFRB at 5q33 (imatinib), FGFR1 at 8p11 (ponatinib), and JAK2 at 9p24 (ruxolitinib). We here report the identification of three new PDGFRB fusion genes in three male MPN-eo patients: MPRIP-PDGFRB in a case with t(5;17)(q33;p11), CPSF6-PDGFRB in a case with t(5;12)(q33;q15), and GOLGB1-PDGFRB in a case with t(3;5)(q13;q33). The fusion proteins identified by 5'-rapid amplification of cDNA ends polymerase chain reaction (PCR) or DNA-based long distance inverse PCR are predicted to contain the TK domain of PDGFRB. The partner genes contain domains like coiled-coil structures, which are likely to cause dimerization and activation of the TK. In all patients, imatinib induced rapid and durable complete remissions.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Eosinofilia/genética , Fusão Gênica , Proteínas de Membrana/genética , Transtornos Mieloproliferativos/genética , Receptor beta de Fator de Crescimento Derivado de Plaquetas/genética , Translocação Genética , Fatores de Poliadenilação e Clivagem de mRNA/genética , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/uso terapêutico , Cromossomos Humanos Par 12/genética , Cromossomos Humanos Par 17/genética , Cromossomos Humanos Par 3/genética , Cromossomos Humanos Par 5/genética , Análise Citogenética , Eosinofilia/tratamento farmacológico , Eosinofilia/patologia , Proteínas da Matriz do Complexo de Golgi , Humanos , Mesilato de Imatinib/uso terapêutico , Hibridização in Situ Fluorescente , Masculino , Pessoa de Meia-Idade , Transtornos Mieloproliferativos/tratamento farmacológico , Transtornos Mieloproliferativos/patologia , Reação em Cadeia da Polimerase , Indução de Remissão
10.
Blood ; 122(14): 2433-42, 2013 Oct 03.
Artigo em Inglês | MEDLINE | ID: mdl-23974200

RESUMO

The transcription factor CCAAT enhancer binding protein α (C/EBPα) is a master regulator in granulopoiesis and is frequently disrupted in acute myeloid leukemia (AML). We have previously shown that C/EBPα exerts its effects by regulating microRNAs (miRs) such as miR-223 and miR-34a. Here, we confirm miR-30c as a novel important target of C/EBPα during granulopoiesis. Thus, wild-type C/EBPα-p42 directly upregulates miR-30c expression, whereas C/EBPα-p30, found in AML, does not. miR-30c is downregulated in AML, especially in normal karyotype AML patients with CEBPA mutations. An induced C/EBPα knockout in mice leads to a significant downregulation of miR-30c expression in bone marrow cells. We identified NOTCH1 as a direct target of miR-30c. Finally, a block of miR-30c prevents C/EBPα-induced downregulation of Notch1 protein and leads to a reduced CD11b expression in myeloid differentiation. Our study presents the first evidence that C/EBPα, miR-30c, and Notch1 together play a critical role in granulocytic differentiation and AML, and particularly in AML with CEBPA mutations. These data reveal the importance of deregulated miRNA expression in leukemia and may provide novel biomarkers and therapeutic targets in AML.


Assuntos
Proteína alfa Estimuladora de Ligação a CCAAT/metabolismo , Granulócitos/citologia , Leucemia Mieloide Aguda/metabolismo , MicroRNAs/metabolismo , Receptor Notch1/metabolismo , Animais , Diferenciação Celular/fisiologia , Imunoprecipitação da Cromatina , Regulação para Baixo , Regulação Neoplásica da Expressão Gênica , Granulócitos/metabolismo , Humanos , Immunoblotting , Leucemia Mieloide Aguda/genética , Leucopoese/fisiologia , Camundongos , Camundongos Knockout , MicroRNAs/genética , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transfecção
11.
Blood ; 122(14): 2460-6, 2013 Oct 03.
Artigo em Inglês | MEDLINE | ID: mdl-23958953

RESUMO

To explore mechanisms contributing to the clinical heterogeneity of systemic mastocytosis (SM) and to suboptimal responses to diverse therapies, we analyzed 39 KIT D816V mutated patients with indolent SM (n = 10), smoldering SM (n = 2), SM with associated clonal hematologic nonmast cell lineage disorder (SM-AHNMD, n = 5), and aggressive SM (n = 15) or mast cell leukemia (n = 7) with (n = 18) or without (n = 4) AHNMD for additional molecular aberrations. We applied next-generation sequencing to investigate ASXL1, CBL, IDH1/2, JAK2, KRAS, MLL-PTD, NPM1, NRAS, TP53, SRSF2, SF3B1, SETBP1, U2AF1 at mutational hotspot regions, and analyzed complete coding regions of EZH2, ETV6, RUNX1, and TET2. We identified additional molecular aberrations in 24/27 (89%) patients with advanced SM (SM-AHNMD, 5/5; aggressive SM/mast cell leukemia, 19/22) whereas only 3/12 (25%) indolent SM/smoldering SM patients carried one additional mutation each (U2AF1, SETBP1, CBL) (P < .001). Most frequently affected genes were TET2, SRSF2, ASXL1, CBL, and RUNX1. In advanced SM, 21/27 patients (78%) carried ≥3 mutations, and 11/27 patients (41%) exhibited ≥5 mutations. Overall survival was significantly shorter in patients with additional aberrations as compared to those with KIT D816V only (P = .019). We conclude that biology and prognosis in SM are related to the pattern of mutated genes that are acquired during disease evolution.


Assuntos
Análise Mutacional de DNA , Mastocitose Sistêmica/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Perfilação da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Nucleofosmina , Proteínas Proto-Oncogênicas c-kit/genética
12.
Haematologica ; 100(8): 1051-7, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-26001790

RESUMO

Next generation sequencing technologies have provided insights into the molecular heterogeneity of various myeloid neoplasms, revealing previously unknown somatic genetic events. In our cohort of 1444 cases analyzed by next generation sequencing, somatic mutations in the gene BRCA1-BRCA2-containing complex 3 (BRCC3) were identified in 28 cases (1.9%). BRCC3 is a member of the JAMM/MPN+ family of zinc metalloproteases capable of cleaving Lys-63 linked polyubiquitin chains, and is implicated in DNA repair. The mutations were located throughout its coding region. The average variant allelic frequency of BRCC3 mutations was 30.1%, and by a serial sample analysis at two different time points a BRCC3 mutation was already identified in the initial stage of a myelodysplastic syndrome. BRCC3 mutations commonly occurred in nonsense (n=12), frameshift (n=4), and splice site (n=5) configurations. Due to the marginal male dominance (odds ratio; 2.00, 0.84-4.73) of BRCC3 mutations, the majority of mutations (n=23; 82%) were hemizygous. Phenotypically, BRCC3 mutations were frequently observed in myelodysplastic syndromes and myelodysplastic/myeloproliferative neoplasms and associated with -Y abnormality (odds ratio; 3.70, 1.25-11.0). Clinically, BRCC3 mutations were also related to higher age (P=0.01), although prognosis was not affected. Knockdown of Brcc3 gene expression in murine bone marrow lineage negative, Sca1 positive, c-kit positive cells resulted in 2-fold more colony formation and modest differentiation defect. Thus, BRCC3 likely plays a role as tumor-associated gene in myelodysplastic syndromes and myelodysplastic/myeloproliferative neoplasms.


Assuntos
Proteínas de Membrana/genética , Mutação , Transtornos Mieloproliferativos/genética , Idoso , Idoso de 80 Anos ou mais , Alelos , Animais , Proteína BRCA1/genética , Aberrações Cromossômicas , Análise Mutacional de DNA , Enzimas Desubiquitinantes , Feminino , Frequência do Gene , Técnicas de Silenciamento de Genes , Estudos de Associação Genética , Genótipo , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Transtornos Mieloproliferativos/diagnóstico , Fenótipo , RNA Interferente Pequeno/genética
13.
Ann Hematol ; 94(12): 1991-2001, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26351014

RESUMO

Germline polymorphisms in genes mutated in acute myeloid leukemia (AML) may have prognostic impact. Therefore, the relevance of the polymorphism IDH1G105 (IDH1105(GGT) minor allele) was evaluated in the context of concomitant molecular mutations in a cohort of 507 AML cases with intermediate-risk cytogenetics. In addition, a cohort of 475 healthy controls was analyzed for this polymorphism. IDH1105(GGT) minor allele was found in 10 % of AML patients and 9 % of healthy controls. While no differences were seen with regard to cytomorphology or cytogenetics, immunophenotyping revealed significantly reduced expression of the progenitor marker CD34 in AML cases harboring IDH1105(GGT) minor allele. Cases with IDH1105(GGT) minor allele as compared to those with the IDH1105(GGC) major allele had significantly longer event-free survival (EFS) (median 16 vs 11 months, p = 0.013) which was most pronounced in the age group >60 years (median 14 vs 9 months, p = 0.007) and in the NPM1 mutated/FLT3-ITD/FLT3wt ratio <0.5 group (median 61 vs 13 months, p = 0.012). However, this association is not independent of other prognostic parameters, and we conclude that IDH1105(GGT) minor allele has to be considered in the context of the genetic background of the individual AML analyzed.


Assuntos
Alelos , Biomarcadores Tumorais/genética , Isocitrato Desidrogenase/genética , Leucemia Mieloide Aguda , Polimorfismo Genético , Adolescente , Adulto , Idoso , Antígenos CD34 , Intervalo Livre de Doença , Feminino , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/mortalidade , Masculino , Pessoa de Meia-Idade , Proteínas Nucleares/genética , Nucleofosmina , Taxa de Sobrevida , Tirosina Quinase 3 Semelhante a fms/genética
14.
Eur J Haematol ; 95(5): 436-41, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25605311

RESUMO

Preemptive treatment of relapse of acute myeloid leukemia (AML) holds the promise to improve the prognosis of this currently highly lethal condition. Proposed treatment modalities applicable in preemptive cytoreduction (e.g., demethylating agents or standard chemotherapy) differ substantially in interval from administration to antileukemic effect. The t(6;9) balanced translocation, producing the DEK-NUP214 fusion protein, is seen in only 1% of patients with AML. We hypothesized that in these patients, who relapse with a very high frequency, a more detailed knowledge of leukemic relapse growth kinetics would improve the personalized decision-making regarding re-administration of chemotherapy. Based on standardized quantitative PCR data, we therefore delineated the relapse kinetics in a cohort of 27 relapsing DEK-NUP214-positive patients treated in four different European countries. The prerelapse leukemic burden increased with a median doubling time of 13 d (range: 5-51 d, median: 0.71 logs/month, range: 0.18-1.91 logs/month), with FLT3-ITD-positive patients relapsing significantly faster than FLT3-ITD-negative ones (median: 0.9 vs. 0.6 logs/month, Wilcoxon rank sum test, P = 0.041). Peripheral blood and bone marrow were equally useful for minimal residual disease (MRD) detection, and thus, we found that with sampling intervals of 2 months, 94% of relapses would be detected with a median time from MRD detection to hematological relapse of 64 d. In conclusion, this data provide algorithms for handling the rare patients with DEK-NUP214-positive AML allowing for planning of both MRD follow-up and, upon molecular relapse, the timing of cytoreduction or possibly transplant procedures.


Assuntos
Algoritmos , Proteínas Cromossômicas não Histona , Leucemia Mieloide Aguda , Modelos Biológicos , Complexo de Proteínas Formadoras de Poros Nucleares , Proteínas de Fusão Oncogênica , Proteínas Oncogênicas , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Proteínas Cromossômicas não Histona/genética , Proteínas Cromossômicas não Histona/metabolismo , Cromossomos Humanos Par 6/genética , Cromossomos Humanos Par 6/metabolismo , Cromossomos Humanos Par 9/genética , Cromossomos Humanos Par 9/metabolismo , Intervalo Livre de Doença , Feminino , Seguimentos , Humanos , Cinética , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/mortalidade , Leucemia Mieloide Aguda/terapia , Masculino , Pessoa de Meia-Idade , Complexo de Proteínas Formadoras de Poros Nucleares/genética , Complexo de Proteínas Formadoras de Poros Nucleares/metabolismo , Proteínas Oncogênicas/genética , Proteínas Oncogênicas/metabolismo , Proteínas de Fusão Oncogênica/genética , Proteínas de Fusão Oncogênica/metabolismo , Proteínas de Ligação a Poli-ADP-Ribose , Recidiva , Taxa de Sobrevida , Translocação Genética
15.
Eur J Haematol ; 95(4): 270-9, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25951317

RESUMO

Since the discovery of the JAK2 V617F mutation in the majority of the myeloproliferative neoplasms (MPN) of polycythemia vera, essential thrombocythemia and primary myelofibrosis ten years ago, further MPN-specific mutational events, notably in JAK2 exon 12, MPL exon 10 and CALR exon 9 have been identified. These discoveries have been rapidly incorporated into evolving molecular diagnostic algorithms. Whilst many of these mutations appear to have prognostic implications, establishing MPN diagnosis is of immediate clinical importance with selection, implementation and the continual evaluation of the appropriate laboratory methodology to achieve this diagnosis similarly vital. The advantages and limitations of these approaches in identifying and quantitating the common MPN-associated mutations are considered herein with particular regard to their clinical utility. The evolution of molecular diagnostic applications and platforms has occurred in parallel with the discovery of MPN-associated mutations, and it therefore appears likely that emerging technologies such as next-generation sequencing and digital PCR will in the future play an increasing role in the molecular diagnosis of MPN.


Assuntos
Transtornos Mieloproliferativos/diagnóstico , Transtornos Mieloproliferativos/genética , Calreticulina/genética , Éxons , Humanos , Janus Quinase 2/genética , Janus Quinase 2/metabolismo , Técnicas de Diagnóstico Molecular/métodos , Técnicas de Diagnóstico Molecular/normas , Mutação , Transtornos Mieloproliferativos/metabolismo , Garantia da Qualidade dos Cuidados de Saúde , Receptores de Trombopoetina/genética
16.
Am J Hematol ; 90(9): 774-7, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26017288

RESUMO

Myeloproliferative neoplasms with eosinophilia are commonly characterized by a normal karyotype and remain poorly defined at the molecular level. We therefore investigated 426 samples from patients with hypereosinophilia of unknown significance initially referred for screening of the FIP1L1-PDGFRA (FP) fusion gene also for KIT D816V and JAK2 V617F mutations. Overall, 86 (20%) patients tested positive: FP+ in 55 (12%), KIT D816V+ in 14 (3%), and JAK2 V617F+ in 17 (4%) patients, respectively. To gain better insight into clinical characteristics, we compared these cases with 31 additional and well-characterized KIT D816V+ eosinophilia-associated systemic mastocytosis (SM-eo) patients enrolled within the "German Registry on Disorders of Eosinophils and Mast cells." Significant differences included younger age, male predominance, and higher eosinophil counts for FP+ cases while abdominal lymphadenopathy, ascites, and serum tryptase levels >100 µg/l were characteristic for those with KIT D816V. Leukocytes, hemoglobin, and splenomegaly did not differ significantly. A median of three additional mutations, most frequently TET2 and SRSF2, were identified in 12/13 KIT D816V+ SM-eo patients with available material indicating a more complex molecular pathogenesis. Median survival was not reached for FP+ cases but was only 26 and 41 months for KIT D816V+ SM and JAK2 V617F+ MPN-eo, respectively. Eosinophilia of ≥2 × 10(9) /l was identified as discriminator for inferior survival in KIT D816V+ and/or JAK2 V617F+ patients (median survival 20 months vs. not reached, P = 0.002). Thus, there is a clear prognostic and therapeutic rationale for detection of KIT D816V and JAK2 V617F in the diagnostic work up of eosinophilia.


Assuntos
Síndrome Hipereosinofílica/genética , Janus Quinase 2/genética , Mastocitose Sistêmica/genética , Mutação , Proteínas Proto-Oncogênicas c-kit/genética , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Substituição de Aminoácidos , Antineoplásicos/uso terapêutico , Ascite/patologia , Proteínas de Ligação a DNA/genética , Dioxigenases , Feminino , Expressão Gênica , Humanos , Síndrome Hipereosinofílica/diagnóstico , Síndrome Hipereosinofílica/tratamento farmacológico , Síndrome Hipereosinofílica/mortalidade , Doenças Linfáticas/patologia , Masculino , Mastócitos/patologia , Mastocitose Sistêmica/diagnóstico , Mastocitose Sistêmica/tratamento farmacológico , Mastocitose Sistêmica/mortalidade , Pessoa de Meia-Idade , Proteínas Nucleares/genética , Proteínas de Fusão Oncogênica/genética , Prognóstico , Proteínas Proto-Oncogênicas/genética , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/genética , Recidiva , Ribonucleoproteínas/genética , Fatores de Processamento de Serina-Arginina , Fatores Sexuais , Análise de Sobrevida , Triptases/sangue , Fatores de Poliadenilação e Clivagem de mRNA/genética
17.
Genes Chromosomes Cancer ; 53(12): 1008-17, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25183446

RESUMO

We aimed at developing novel assays for Loss of Heterozygosity (LOH) detection on 13q as a substitute for FLT3-ITD analysis to identify acute myeloid leukemia (AML) patients with high risk of shorter survival. To this aim, we first analyzed a selected cohort of 185 patients with (n = 138) or without (n = 47) FLT3-ITD by short tandem repeat (STR) analysis for 13q LOH. In 46 of 138 FLT3-ITD positive cases, a FLT3-ITD/FLT3wt ratio of ≥ 1 was measured indicating LOH. Applying analysis with a combination of five different STR markers, a threshold of an STR allelic ratio of >65% allows the identification of LOH in 40/46 (87%) samples. Survival analysis revealed significantly inferior outcome in patients with LOH as detected by STR analysis (event free survival (EFS): no LOH: 13.3 months versus LOH: 4.5 months, p < 0.001; overall survival (OS): no LOH: 35.8 months versus LOH: 9.7 months, p = 0.001). In multivariate Cox regression analysis, 13q LOH was found to be an independent adverse parameter for EFS and OS (p = 0.003 and p < 0.001, respectively) besides age and white blood cell count. Thus, the prognostic impact of 13q LOH is nearly identical to the one of FLT3-ITD/FLT3wt load of ≥ 1 and thus is a feasible alternative to identify respective patients with high risk AML. In a second approach, a cohort of 91 patients was subjected to a proof-of-principle study of applying single nucleotide polymorphism analysis by next generation amplicon sequencing for detection of LOH. 53/91 cases had LOH and 50 were identified with this new method resulting in a positive detection rate of 94.3%.


Assuntos
Cromossomos Humanos Par 13/genética , Leucemia Mieloide Aguda/diagnóstico , Perda de Heterozigosidade , Tirosina Quinase 3 Semelhante a fms/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Feminino , Humanos , Leucemia Mieloide Aguda/patologia , Masculino , Repetições de Microssatélites , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Prognóstico , Análise de Sequência de DNA , Adulto Jovem
18.
Genes Chromosomes Cancer ; 53(5): 402-10, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-24493299

RESUMO

We analyzed 1,200 patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) harboring a 5q deletion in order to clarify whether the type of 5q loss is associated with other biological markers and prognosis. We investigated all patients by chromosome banding analysis, FISH with a probe for EGR1 (5q31) and, if necessary, to resolve complex karyotypes with 24-color-FISH. Moreover, 420 patients were analyzed for mutations in the TP53 gene. The patient cohort was subdivided based on type of 5q loss: Patients with interstitial deletions and patients with 5q loss due to unbalanced rearrangements or monosomy 5. Loss of the long arm of chromosome 5 due to an unbalanced rearrangement occurred more often in AML (286/627; 45.6%) than MDS (188/573; 32.8%; P < 0.001). In both entities, patients with 5q loss due to unbalanced translocations showed complex karyotypes more frequently (MDS: 179/188; 95.2% vs. 124/385; 32.2%; P < 0.001; AML: 274/286; 95.8% vs. 256/341; 75.1%; P < 0.001). Moreover, in MDS unbalanced 5q translocations were associated with clonal evolution (109/188; 58.0% vs. 124/385; 32.2%; P < 0.001), mutation of TP53 (64/67; 95.5% vs. 40/120; 40.0%; P < 0.001), and shorter survival (15.3 months vs. not reached; P < 0.001). In MDS, complex karyotype was an independent adverse prognostic factor (HR = 5.34; P = 0.032), whereas in AML presence of TP53 mutations was the strongest adverse prognostic factor (HR = 2.21; P = 0.026). In conclusion, in AML and MDS, loss of the long arm of chromosome 5 due to unbalanced translocations is associated with complex karyotype and in MDS, moreover, with clonal evolution, mutations in the TP53 gene and adverse prognosis.


Assuntos
Cariótipo Anormal , Deleção Cromossômica , Cromossomos Humanos Par 5/genética , Evolução Clonal , Leucemia Mieloide Aguda/genética , Síndromes Mielodisplásicas/genética , Translocação Genética , Proteína Supressora de Tumor p53/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Proteína 1 de Resposta de Crescimento Precoce/genética , Estudos de Associação Genética , Humanos , Leucemia Mieloide Aguda/diagnóstico , Pessoa de Meia-Idade , Mutação , Síndromes Mielodisplásicas/diagnóstico , Prognóstico
19.
Genes Chromosomes Cancer ; 53(6): 524-36, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24619868

RESUMO

B lymphoblastic leukemia/lymphoma (ALL) are subdivided by the WHO classification into five subgroups defined by specific translocations and two further subgroups defined by the number of chromosomes. The hypodiploid subgroup is heterogeneous and comprises ALL with a chromosome number of <46. To characterize a specific subset with low hypodiploid karyotype, we performed chromosome banding analysis, FISH, array comparative genomic hybridization, and mutational analyses of FBXW7, NOTCH1, KRAS, NRAS, TP53, and IKZF1 in 29 cases. We observed a nonrandom pattern of chromosome losses, including chromosomes 3, 7, 13, 15, 16, and 17. A deletion encompassing the CDKN2A/B locus was the only recurrent structural abnormality. A duplication of the low hypodiploid karyotype occurred frequently, resulting in a near triploid karyotype based on the definition by merely counting chromosomes but in fact was a very low tetraploid chromosome set. Mutational analyses revealed no mutations in IKZF1, FBXW7, NOTCH1, and KRAS and only one mutation in NRAS. However, we discovered a high frequency of TP53 mutations in 93% (27/29) of cases. In 26/27 cases with TP53 mutation, the second TP53 allele was lost due to monosomy 17. Median overall survival was short (18.5 months), which might be related to the high frequency of TP53 alterations. Therefore, ALL with low hypodiploidy is characterized by a typical pattern of chromosome losses and a remarkably high TP53 mutation frequency. Our data suggest the introduction of a novel WHO entity within the B lymphoblastic leukemia/lymphoma group showing low hypodiploid/very low tetraploid karyotype and concomitant TP53 mutation.


Assuntos
Cariótipo Anormal , Taxa de Mutação , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Triploidia , Proteína Supressora de Tumor p53/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Hibridização in Situ Fluorescente , Cariotipagem , Masculino , Pessoa de Meia-Idade , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Proteína Supressora de Tumor p53/metabolismo , Adulto Jovem
20.
Hum Mutat ; 35(1): 15-26, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-24115288

RESUMO

Congenital erythrocytosis (CE), or congenital polycythemia, represents a rare and heterogeneous clinical entity. It is caused by deregulated red blood cell production where erythrocyte overproduction results in elevated hemoglobin and hematocrit levels. Primary congenital familial erythrocytosis is associated with low erythropoietin (Epo) levels and results from mutations in the Epo receptor gene (EPOR). Secondary CE arises from conditions causing tissue hypoxia and results in increased Epo production. These include hemoglobin variants with increased affinity for oxygen (HBB, HBA mutations), decreased production of 2,3-bisphosphoglycerate due to BPGM mutations, or mutations in the genes involved in the hypoxia sensing pathway (VHL, EPAS1, and EGLN1). Depending on the affected gene, CE can be inherited either in an autosomal dominant or recessive mode, with sporadic cases arising de novo. Despite recent important discoveries in the molecular pathogenesis of CE, the molecular causes remain to be identified in about 70% of the patients. With the objective of collecting all the published and unpublished cases of CE the COST action MPN&MPNr-Euronet developed a comprehensive Internet-based database focusing on the registration of clinical history, hematological, biochemical, and molecular data (http://www.erythrocytosis.org/). In addition, unreported mutations are also curated in the corresponding Leiden Open Variation Database.


Assuntos
Bases de Dados Genéticas , Predisposição Genética para Doença , Mutação , Policitemia/congênito , Receptores da Eritropoetina/genética , Hipóxia Celular/genética , Eritropoetina/metabolismo , Humanos , Internet , Policitemia/genética , Policitemia/metabolismo , Transdução de Sinais/genética
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