RESUMO
Despite the recent advances, the clinical approach to persistent pulmonary hypertension of the newborn (PPHN) still represents an important challenge for neonatologists. The care of newborns with PPHN requires meticulous therapeutic and ventilation strategies including, besides the stabilization of the newborn, the use of nitric oxide and high-frequency ventilation. However, not all the neonates with PPHH are responsive to this clinical approach. Recent studies have proposed the use of sildenafil, a phosphodiesterase 5 inhibitor, in refractory forms of PPHN. The aim of this study is to review the cases and the clinical approach of PPHN in the Neonatal Intensive Care Unit of Meyer Children Hospital in the year 2009 and to discuss the possible role of sildenafil in the management of PPHN.
Assuntos
Síndrome da Persistência do Padrão de Circulação Fetal/tratamento farmacológico , Piperazinas/uso terapêutico , Sulfonas/uso terapêutico , Anti-Hipertensivos/uso terapêutico , Idade Gestacional , Humanos , Recém-Nascido , Tempo de Internação/estatística & dados numéricos , Síndrome da Persistência do Padrão de Circulação Fetal/mortalidade , Purinas/uso terapêutico , Estudos Retrospectivos , Citrato de Sildenafila , Vasodilatadores/uso terapêuticoRESUMO
The PAX5 gene, encoding the B-cell-specific activator protein, is a critical determinant of commitment to the B-lymphocyte pathway. This gene, mapped at 9p13, is juxtaposed to the immunoglobulin heavy chain (IgH) gene as a result of the t(9;14)(p13;q32), a rare but recurring translocation found in a subset of B-cell non-Hodgkin's lymphoma cases. In all of these, this translocation results in deregulated expression of the gene product because of the proximity of IgH. We present here the molecular characterization of a previously reported acute lymphoblastic leukemia case carrying a t(9;12)(q11;p13) translocation. Using 5' rapid amplification of cDNA ends PCR, a novel chimeric transcript was identified that contained the NH(2)-terminal region of PAX5 and most of the ETV6/TEL gene on 12p13. According to the fusion transcript, the resulting chimeric protein would retain the PAX5 paired-box domain and both the helix-loop-helix and DNA binding domains of TEL. Thus, it is reasonable to hypothesize that this protein could act as an aberrant transcription factor. This is the first report of PAX5 rearrangement in a human malignancy resulting in a chimeric transcript.
Assuntos
Proteínas de Ligação a DNA/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Proteínas/genética , Proteínas Repressoras , Fatores de Transcrição/genética , Sequência de Bases , Northern Blotting , Cromossomos Humanos Par 12 , Cromossomos Humanos Par 9 , Humanos , Hibridização in Situ Fluorescente , Dados de Sequência Molecular , Fator de Transcrição PAX5 , Proteínas Proto-Oncogênicas c-ets , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Translocação Genética , Variante 6 da Proteína do Fator de Translocação ETSRESUMO
The Ets variant gene 6 (ETV6/TEL) gene is rearranged in the majority of patients with 12p13 translocations fused to a number of different partners. We present here a case of acute myeloid leukemia M4 with eosinophilia (AML-M4Eo) positive for the CBFb/MYH11 rearrangement and carrying a t(1;12)(q25;p13) that involves the ETV6 gene at 12p13. By 3'rapid amplification of cDNA ends-polymerase chain reaction (3'RACE-PCR), a novel fusion transcript was identified between the ETV6 and the Abelson-related gene (ARG) at 1q25, resulting in a chimeric protein consisting of the HLH oligomerization domain of ETV6 and the SH2, SH3, and protein tyrosine kinase (PTK) domains of ARG. The reciprocal transcript ARG-ETV6 was also detected in the patient RNA by reverse transcriptase-polymerase chain reaction (RT-PCR), although at a lower expression level. The ARG gene encodes for a nonreceptor tyrosine kinase characterized by high homology with c-Abl in the TK, SH2, and SH3 domains. This is the first report on ARG involvement in a human malignancy.
Assuntos
Cromossomos Humanos Par 12 , Cromossomos Humanos Par 1 , Proteínas de Ligação a DNA/genética , Genes abl , Leucemia Mieloide/genética , Proteínas Tirosina Quinases/genética , Proteínas Repressoras , Fatores de Transcrição/genética , Translocação Genética , Feminino , Humanos , Pessoa de Meia-Idade , Proteínas de Fusão Oncogênica/genética , Proteínas Proto-Oncogênicas c-ets , Variante 6 da Proteína do Fator de Translocação ETSRESUMO
BACKGROUND: There is little current insight into the natural history of childhood leukaemia or the timing of relevant mutational events. TEL-AML1 gene fusion due to chromosomal translocation is frequently seen in the common form of childhood acute lymphoblastic leukaemia. We investigated whether this abnormality arises prenatally. METHODS: We identified, by reverse-transcriptase PCR screening of blood or bone marrow, TEL-AML1 fusion in 12 children, plus a pair of identical twins, aged 2-5 years from Italy and the UK, who had newly diagnosed acute lymphoblastic leukaemia. We amplified and sequenced the genomic TEL-AML1 fusion gene with a long-distance inverse PCR method. Primers were designed that could be used in short-range PCR to screen for patient-specific, leukaemia clone-specific TEL-AML1 genomic fusion sequences in neonatal blood spots from each child. FINDINGS: We initially identified TEL-AML1 fusion sequences in blood spots from the identical twins, diagnosed with concordant acute lymphoblastic leukaemia at age 4 years, who shared a single or clonotypic TEL-AML1 sequence that suggested prenatal origin in one twin. Three children were excluded because control genes could not be amplified. Of the other nine patients, six had positive blood spots. Blood spots that were classified as negative were uninformative. INTERPRETATION: Our findings showed that childhood acute lymphoblastic leukaemia is frequently initiated by a chromosome translocation event in utero. Studies in identical twins show however that such an event is insufficient for clinical leukaemia and that a postnatal promotional event is also required.