RESUMO
In silico analysis is a promising approach for understanding biological events in complex diseases. Herein we report on the innovative computational workflow allowed to highlight new direct interactions between human transcription factors (TFs) and an entire genome of virus ZikaSPH2015 strain in order to identify the occurrence of specific motifs on a genomic Zika Virus sequence that is able to bind and, therefore, sequester host's TFs. The analysis pipeline was performed using different bioinformatics tools available online (free of charge). According to obtained results of this in silico analysis, it is possible to hypothesize that these TFs binding motifs might be able to explain the complex and heterogeneous phenotype presentation in Zika-virus-affected fetuses/newborns, as well as the less severe condition in adults. Moreover, the proposed in silico protocol identified thirty-three different TFs identical to the distribution of TFBSs (Transcription Factor Binding Sites) on ZikaSPH2015 strain, potentially able to influence genes and pathways with biological functions confirming that this approach could find potential answers on disease pathogenesis.
RESUMO
BACKGROUND: The t(9;22)(q34;q11), generating the Philadelphia (Ph) chromosome, is found in more than 90% of patients with chronic myeloid leukemia (CML). As a result of the translocation, the 3' portion of the ABL1 oncogene is transposed from 9q34 to the 5' portion of the BCR gene on chromosome 22 to form the BCR/ABL1 fusion gene. At diagnosis, in 5-10% of CML patients the Ph chromosome is derived from variant translocations other than the standard t(9;22). RESULTS: We report a molecular cytogenetic study of 452 consecutive CML patients at diagnosis, that revealed 50 cases identifying three main subgroups: i) cases with variant chromosomal rearrangements other than the classic t(9;22)(q34;q11) (9.5%); ii) cases with cryptic insertions of ABL1 into BCR, or vice versa (1.3%); iii) cases bearing additional chromosomal rearrangements concomitant to the t(9;22) (1.1%). For each cytogenetic group, the mechanism at the basis of the rearrangement is discussed.All breakpoints on other chromosomes involved in variant t(9;22) and in additional rearrangements have been characterized for the first time by Fluorescence In Situ Hybridization (FISH) experiments and bioinformatic analyses. This study revealed a high content of Alu repeats, genes density, GC frequency, and miRNAs in the great majority of the analyzed breakpoints. CONCLUSIONS: Taken together with literature data about CML with variant t(9;22), our findings identified several new cytogenetic breakpoints as hotspots for recombination, demonstrating that the involvement of chromosomes other than 9 and 22 is not a random event but could depend on specific genomic features. The presence of several genes and/or miRNAs at the identified breakpoints suggests their potential involvement in the CML pathogenesis.
Assuntos
Pontos de Quebra do Cromossomo , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Translocação Genética , Antineoplásicos/uso terapêutico , Benzamidas , Cromossomos Humanos Par 22/genética , Cromossomos Humanos Par 9/genética , Dasatinibe , Proteínas de Fusão bcr-abl/genética , Humanos , Mesilato de Imatinib , Hibridização in Situ Fluorescente , Interferon-alfa/uso terapêutico , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Piperazinas/uso terapêutico , Pirimidinas/uso terapêutico , Tiazóis/uso terapêuticoRESUMO
The t(9;22)(q34;q11), generating the Philadelphia chromosome, is found in more than 90% of patients with chronic myelocytic leukemia (CML). Deletions adjacent to the translocation breakpoint on the derivative chromosome 9 have been described by several groups. These studies revealed two primary points: (1) genomic microdeletions were concomitant with the t(9;22) rearrangement; and (2) the location of the deleted sequence was centromeric to ABL and telomeric to BCR genes. We report on a detailed molecular cytogenetic characterization of chromosomal rearrangements in two CML patients bearing a complex variant t(9;22) and insertions of chromosome 22 sequences in 9q34. Our study shows that the location of the deleted sequences was downstream of the ABL gene and that genomic microdeletions were concomitant with the ins(9;22)(q34;q11q11) rearrangement.
Assuntos
Deleção Cromossômica , Cromossomos Humanos Par 9 , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Cromossomo Filadélfia , Adulto , Aberrações Cromossômicas , Cromossomos Humanos Par 22/ultraestrutura , Cromossomos Humanos Par 9/ultraestrutura , Feminino , Proteínas de Fusão bcr-abl/genética , Genes abl , Humanos , Hibridização in Situ Fluorescente , Leucemia Mielogênica Crônica BCR-ABL Positiva/diagnóstico , Masculino , Pessoa de Meia-Idade , Proteínas Proto-Oncogênicas c-bcr/genéticaAssuntos
Aberrações Cromossômicas , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/mortalidade , Tirosina Quinase 3 Semelhante a fms/genética , Idoso , Idoso de 80 Anos ou mais , Intervalo Livre de Doença , Feminino , Humanos , Cariotipagem , Leucemia Mieloide Aguda/terapia , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Taxa de SobrevidaRESUMO
The 22q11.2 microduplication is a genomic disorder, characterized from a variable phenotype ranging from different defects to normality. The most common microduplication of 22q11.2 is 3 Mb in size, but there are also cases reported with atypical duplications between 0.8 Mb and 6Mb. Here, we describe a case of a child with macrocephaly, overgrowth with advanced bone age, attention deficits, evidence of mild mental retardation and dysmorphic features. An array-CGH analysis detected a 252 Kb duplication at the 22q11.2 region inherited from mother and 142 Kb duplication at 8q22.1 region inherited from father. Both parents show mild dysmorphic features. The duplicated genes in chromosomes 22q and 8q are TOP3B and PGCP, respectively. We describe for the first time a patient carrying the smaller atypical 22q11.2 duplication who also presents with mild mental retardation and generalized overgrowth. This patient has an additional duplication in 8q22.1 which may act as a genomic modifier of its clinical phenotype.
Assuntos
Anormalidades Múltiplas/genética , Duplicação Cromossômica/genética , Síndrome de DiGeorge/genética , Transtornos do Crescimento/genética , Deficiência Intelectual/genética , Trissomia/genética , Adolescente , Adulto , Cromossomos Humanos Par 22/genética , Cromossomos Humanos Par 8/genética , Feminino , Humanos , MasculinoAssuntos
Leucemia Mieloide/induzido quimicamente , Leucemia Mieloide/genética , Leucemia Promielocítica Aguda/complicações , Doença Aguda , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Cromossomos Humanos Par 11 , Cromossomos Humanos Par 9 , Feminino , Humanos , Leucemia Promielocítica Aguda/terapia , Segunda Neoplasia Primária/induzido quimicamente , Segunda Neoplasia Primária/genética , Translocação Genética , Tretinoína/efeitos adversosRESUMO
The t(11;14)(q13;q32) is a hallmark of mantle cell lymphoma. It has been found less frequently in other lymphoproliferative disorders, such as B-prolymphocytic leukemia, plasma cell leukemia, chronic lymphocytic leukemia, and multiple myeloma. Here, we describe a patient with acute myeloid leukemia (AML), categorized as M5b according to French-American-British classification, in which conventional cytogenetic analysis revealed a karyotype with t(11;14)(q13;q32). Fluorescence in situ hybridization analyses demonstrated no rearrangement of the immunoglobulin heavy-chain (IGH) (14q32) locus as well as of the cyclin D1 (CCND1) gene, suggesting that this is not the typical t(11;14) resulting from the CCND1/IGH fusion. The changes in the 11q13 region have been described in both myeloid and lymphoid neoplasm with different chromosomes serving as donors in translocation, but to the best of our knowledge, never with the chromosome 14.
Assuntos
Ciclina D1/genética , Cadeias Pesadas de Imunoglobulinas/genética , Leucemia Mieloide Aguda/genética , Translocação Genética , Medula Óssea/patologia , Feminino , Humanos , Cariotipagem , Leucemia Mieloide Aguda/patologia , Pessoa de Meia-IdadeRESUMO
The upper age limit for autologous stem cell transplantation (ASCT) in acute myeloid leukemia (AML) is increasing and peripheral blood (PB) represents the standard source of stem cell (SC). However, no data are available on the impact of age on SC mobilization in AML. We analyzed a cohort of 150 consecutive AML patients in first complete remission in order to make a comparison between patients up to 60 years and above 60 years, by evaluating CD34+ cells mobilization into PB and the number of leukapheresis needed to collect at least one single SC graft. The successful mobilization rate (>2 x 10(6) CD34+ cells/kg) was comparable between the two groups (87% vs. 80%, p = 0.29). In addition, no statistically significant difference was found in terms of either median number of CD34+ cells collected (p = 0.54) or CD34+ cells peak in PB (p = 0.70). Both groups of patients needed a median of two apheresis and no difference was found in the median number of CD34+ cells collected per single apheresis (p = 0.67). Finally, no correlation was found between age and total number of CD34+ cells collected (r = 0.003, p = 0.58). We conclude that age has no impact on mobilization of PBSCs in AML.
Assuntos
Mobilização de Células-Tronco Hematopoéticas , Leucemia Mieloide Aguda/sangue , Transplante de Células-Tronco de Sangue Periférico , Adolescente , Adulto , Fatores Etários , Idoso , Feminino , Humanos , Leucemia Mieloide Aguda/terapia , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Transplante AutólogoRESUMO
Several studies have reported data on factors influencing mobilization of peripheral blood stem cells (PBSC) in non-myeloid malignancies. On the contrary, data from patients with acute myeloid leukemia (AML) are very limited, in particular, as the impact of an antecedent diagnosis of refractory anemia with excess blasts (RAEB) on mobilization of PBSCs as well as hematopoietic recovery after autologous stem cell transplantation (ASCT) is concerned. We retrospectively analyzed a cohort of 150 consecutive AML patients in first complete remission in order to make a comparison between patients with de novo AML and secondary AML (s-AML) in terms of CD34 positive (CD34+) cells mobilization and number of leukapheresis needed to collect at least one single stem cell graft. Data concerning hematopoietic recovery after ASCT were also compared. The successful mobilization rate (>2 x 10(6) CD34+ cells/kg) was comparable between de novo AML patients (87%) and those with s-AML (76%), P:0.21. No statistically significant difference was found in terms of either median number of CD34+ cells collected (P:0.44) or CD34+ cells peak in peripheral blood (P:0.28). Both groups of patients needed a median of two apheresis (P:0.45) and no difference was found on the median number of CD34+ cells collected per single apheresis (P:0.59). Finally, neutrophil and platelet recovery after ASCT were comparable between the two groups. An antecedent diagnosis of RAEB has no impact on mobilization and collection of PBSCs in AML as well as on hematopoietic recovery after ASCT.
Assuntos
Anemia Refratária com Excesso de Blastos/diagnóstico , Hematopoese , Mobilização de Células-Tronco Hematopoéticas , Leucemia Mieloide/terapia , Transplante de Células-Tronco de Sangue Periférico , Doença Aguda , Adolescente , Adulto , Idoso , Intervalo Livre de Doença , Feminino , Humanos , Leucemia Mieloide/diagnóstico , Leucemia Mieloide/etiologia , Masculino , Pessoa de Meia-Idade , Transplante Autólogo , Resultado do TratamentoRESUMO
In this study, we analysed the prognostic relevance of foetal liver tyrosine kinase 3 (FLT3) mutations in 73 patients with acute myeloid leukaemia (AML) with normal karyotype, who survived induction and consolidation and received autologous stem cell transplantation (ASCT) after successful mobilization of peripheral blood stem cell (PBSC). There were 44 males and 29 females with a median age of 54 years (range 20-77). Overall, 16 out of 73 autografted patients (22%) had FLT3 mutations. More in detail, FLT3/ITDs were detected in 10 out of 73 patients (14%), while FLT3 D835 mutations were detected in five cases (7%). One patient (1%) was found as having both abnormalities. White blood cell count (p=0.009), serum concentration of lactate dehydrogenase (p=0.01), and percentages of peripheral blood (p=0.002) and bone marrow blasts (p=0.03) were significantly higher in patients showing the FLT3 mutations. On the contrary, overall survival and disease-free survival were similar between patients with or without FLT3 mutations (p=0.73 and 0.78, respectively). In conclusion, our data suggest that myeloablative chemotherapy supported by auto-PBSCT may overcome the adverse prognostic implications of FLT3 mutations in AML. However, it is to consider that autografted patients are highly selected for best response to induction, consolidation and mobilization, as well as for minor non-haematologic toxicity.
Assuntos
Transplante de Células-Tronco Hematopoéticas , Leucemia Mieloide/diagnóstico , Mutação , Agonistas Mieloablativos/uso terapêutico , Tirosina Quinase 3 Semelhante a fms/genética , Doença Aguda , Adulto , Idoso , Antineoplásicos/uso terapêutico , Feminino , Humanos , Cariotipagem , Leucemia Mieloide/mortalidade , Leucemia Mieloide/terapia , Masculino , Pessoa de Meia-Idade , Prognóstico , Indução de Remissão , Análise de Sobrevida , Sequências de Repetição em Tandem , Transplante AutólogoRESUMO
Fetal liver tyrosine kinase 3 (FLT3) mutations represent a powerful prognostic indicator in acute myeloid leukemia (AML). Further, interaction between FLT3 and its ligand plays a role in normal hematopoiesis. Accordingly, FLT3 mutations may affect mobilization of peripheral blood stem cells (PBSCs) and feasibility of autologous stem cell transplantation (ASCT) in AML. We analyzed the effect of FLT3 mutations on mobilization of CD34(+) cells and on PBASCT feasibility from 111 patients with AML, with a median age of 58 years and normal karyotype. Overall, 23 patients (21%) had FLT3 mutations. The complete remission rate was 74% and was not influenced by FLT3 mutations (73% for patients with FLT3(-) and 78% for those with FLT3(+); P= .78). The successful mobilization rate was 79% and was comparable for patients with FLT3(-) and with FLT3(+) (P = .42). Median numbers of CD34(+) cells collected were 7.6 x 10(6)/kg and 7.1 x 10(6)/kg for patients with FLT3(-) and those with FLT3(+), respectively (P = .64). Among 73 patients evaluated for mobilization, feasibility of ASCT was 71%, and there was no difference between patients with FLT3(-) (74%) and those with FLT3(+) (61%), P = .43. We conclude that the FLT3 mutations have no influence on mobilization of CD34(+) cells or on feasibility of PBASCT in patients with AML and normal karyotype.