Assuntos
Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Lectina de Ligação a Manose/deficiência , Polimorfismo de Nucleotídeo Único , Doença Aguda , Adolescente , Aloenxertos , Criança , Pré-Escolar , Intervalo Livre de Doença , Feminino , Doença Enxerto-Hospedeiro/sangue , Doença Enxerto-Hospedeiro/genética , Doença Enxerto-Hospedeiro/mortalidade , Humanos , Masculino , Taxa de SobrevidaRESUMO
Despite their apparently good prognosis â¼15% of high hyperdiploid (HD) childhood acute lymphoblastic leukemia (ALL) cases relapse. To search for responsible risk factors we determined copy number aberrations as well as copy neutral loss of heterozygosity (LOH) in 13 matched diagnosis and relapse samples and added the data of the only three available cases from the literature. Deletions and copy neutral LOH in 3 and 2 of the 16 cases directed us to the histone-modifying CREB-binding protein (CREBBP) gene, whose functional impairment is implicated in drug resistance. We therefore screened all samples for mutations in this gene and discovered 9 acquired sequence mutations in 7/16 cases, leading to an overall frequency of somatic CREBBP aberrations in HD ALL relapse cases of 63% that is considerably higher than that of the reported, mainly non-HD ALL (18.3%). Moreover, mutations in HD cases occur almost exclusively in the HAT domain (8/9; 89%). Hot spot mutations are present at diagnosis in 18.8% of relapsing HD ALL cases but in none of 40 respective cases remaining in long-term remission. Thus, the particular high incidence of CREBBP mutations in relapse-prone HD ALL cases could eventually be exploited for refined risk stratification and customized treatment in this genetic subgroup.
Assuntos
Proteína de Ligação a CREB/genética , Mutação , Ploidias , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Adolescente , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Sequência de Bases , Criança , Pré-Escolar , Variações do Número de Cópias de DNA , Feminino , Humanos , Perda de Heterozigosidade , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Estrutura Terciária de Proteína/genética , Recidiva , Resultado do TratamentoRESUMO
CLTA4 is relevant for FOXP3(+)Treg cells, and the link between skewed X chromosome inactivation (XCI) and autoimmunity is recognized. The observation of immune dysregulation polyendocrinopathy enteropathy X-linked syndrome and multiorgan endocrine autoimmune phenomena in various members of one family, associated with a CTLA4 polymorphism and skewed XCI, provides an in vivo model of how mechanisms of immune dysregulation may cooperate.
