RESUMO
Pediatric acute myeloid leukemia (AML) is a rare disease whose prognosis is highly variable according to factors such as chromosomal abnormalities. Recurrent genomic rearrangements are detected in half of pediatric AML by karyotype. NUcleoPorin 98 (NUP98) gene is rearranged with 31 different fusion partner genes. These rearrangements are frequently undetected by conventional cytogenetics, as the NUP98 gene is located at the end of the chromosome 11 short arm (11p15). By screening a series of 574 pediatric AML, we detected a NUP98 rearrangement in 22 cases (3.8%), a frequency similar to CBFB-MYH11 fusion gene (4.0%). The most frequent NUP98 fusion gene partner is NSD1. These cases are homogeneous regarding their biological and clinical characteristics, and associated with bad prognosis only improved by bone marrow transplantation. We detailed the biological characteristics of these AML by exome sequencing which demonstrated few recurrent mutations (FLT3 ITD, WT1, CEBPA, NBPF14, BCR and ODF1). The analysis of the clonal structure in these cases suggests that the mutation order in the NUP98-rearranged pediatric AML begins with the NUP98 rearrangement leading to epigenetic dysregulations then followed by mutations of critical hematopoietic transcription factors and finally, activation of the FLT3 signaling pathway.
Assuntos
Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/genética , Complexo de Proteínas Formadoras de Poros Nucleares/genética , Translocação Genética , Alelos , Biomarcadores Tumorais , Proteínas Estimuladoras de Ligação a CCAAT/genética , Criança , Pré-Escolar , Epigênese Genética , Exoma , Feminino , Regulação Leucêmica da Expressão Gênica , Frequência do Gene , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Hibridização in Situ Fluorescente , Lactente , Recém-Nascido , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/mortalidade , Masculino , Mutação , Proteínas de Fusão Oncogênica/genética , Prognóstico , Transdução de Sinais , Proteínas WT1/genética , Tirosina Quinase 3 Semelhante a fms/metabolismoRESUMO
We studied the transplacental transfer of epirubicin, an anthracycline used for the treatment of different neoplastic disorders, in particular breast cancers, by in vitro perfusion of term human placenta. Placenta from women with uncomplicated pregnancy were collected immediately after vaginal delivery and put into 37 degrees C thermostated hood. Perfusion of foetal surface of the placenta by modified Earle's solution was started immediately after catheterisation at a flow rate of 6 ml/min and then so was the perfusion of the intervillous space at the rate of 12 ml/min. Samples were collected at different times after the initiation of the perfusion from arterial inflow and venous outflow respective of the maternal and foetal compartment. The transplacental transfer of epirubicin was investigated for two doses: 5 and 9 micrograms/ml. The mean transfer value of epirubicin is low (3.66 +/- 1.07%) for the two tested doses and is only slightly higher than doxorubicin transfer, which drug has provided rare accidents in the clinical reports. These results are in favour of a low placental toxicity of epirubicin. Clinical data have to be collected from pregnant women to confirm the low foetal toxicity of epirubicin.