RESUMEN
Hereditary thrombocythemia is a rare autosomal dominant disorder caused by mutations in either the thrombopoietin gene (TPO) or its receptor c-MPL. TPO mutations described so far lead to thrombopoietin overproduction through increased translation of m-RNA. Unilateral transverse reduction limb defects are usually sporadic and generally thought to be caused by vascular disruptions. Reports of inherited unilateral limb defects are extremely rare. In the present study, we describe a family with segregation of G185T TPO mutation in the 5' UTR region in 4 subjects with thrombocythemia. Three of these patients also present congenital transverse limb defects. Association of these events gives a strong hint of the in vivo involvement of thrombopoietin in vasculogenesis, confirming the role of TPO in human development of the hemangioblast, the embryonic progenitor of the hematopoietic and endothelial lineages. This is the first report showing that vascular disruptions could be secondary to specific gene derangements.
Asunto(s)
Deformidades Congénitas de las Extremidades/complicaciones , Deformidades Congénitas de las Extremidades/genética , Trombocitosis/complicaciones , Trombocitosis/genética , Trombopoyetina/genética , Secuencia de Bases , Análisis Mutacional de ADN , Femenino , Humanos , Lactante , Masculino , Mutación Missense , Linaje , EmbarazoRESUMEN
The MLL-AF9 oncogene originates from the translocation t(9;11)(p22;q23), which is mainly associated with monocytic acute myeloid leukaemia (AML-M5; FAB-classification). In AML-M5 THP-1 cells carrying t(9;11) (p22;q23) and expressing MLL-AF9, we previously showed that MLL-AF9 expression is down-regulated during monocyte-macrophage maturation. We have subsequently observed that in a 'rapid-growing' variant of the THP-1 cell line (THP-1-R) MLL-AF9 down-regulation does not occur. MLL fusion proteins (including MLL-AF9) deregulate MYC transactivation activity, and both presence and absence of MYC down-regulation have been reported during monocyte-macrophage maturation in THP-1 cells. In the present study, we analyze the expression patterns of MLL-AF9, MLL wild-type and MYC after induction of monocyte-macrophage terminal differentiation in the AML-M5 cell lines, THP-1, THP-1-R, Mono-Mac-6 (MM6) and MOLM-13, all of which carry t(9;11)(p22;q23) and express MLL-AF9. RT-PCR analysis indicated that down-regulation of MLL-AF9, MLL or MYC is not necessary to abolish malignant phenotypes by induction of terminal monocyte-macrophage differentiation in leukaemic cells carrying t(9;11)(p22;q23).
Asunto(s)
Leucemia Monocítica Aguda/genética , Macrófagos/citología , Monocitos/citología , Proteína de la Leucemia Mieloide-Linfoide/genética , Proteínas de Fusión Oncogénica/genética , Proteínas Proto-Oncogénicas c-myc/genética , Diferenciación Celular/genética , Cromosomas Humanos Par 11/genética , Cromosomas Humanos Par 9/genética , Regulación hacia Abajo , N-Metiltransferasa de Histona-Lisina , Humanos , Leucemia Monocítica Aguda/inmunología , Translocación GenéticaAsunto(s)
Línea Celular Tumoral/química , Proteínas de Fusión Oncogénica/genética , Empalme Alternativo , ADN de Neoplasias/química , Proteínas de Unión al ADN/genética , N-Metiltransferasa de Histona-Lisina , Humanos , Datos de Secuencia Molecular , Proteína de la Leucemia Mieloide-Linfoide , Proteínas Nucleares/genética , Proto-Oncogenes/genética , ARN Mensajero , Proteínas Recombinantes de Fusión/genética , Análisis de Secuencia de ADN , Factores de Transcripción/genéticaRESUMEN
The translocation t(9;11)(p22;q23) generates the MLL-AF9 oncogene and is commonly associated with monocytic acute myeloid leukemia (AML-M5; FAB-classification). For the oncogenicity of MLL-AF9, the (over)expression of several other genes, including selected HOXA cluster genes as well as MEIS1 (a HOX cofactor), is required. We previously showed that the down-regulation of MLL-AF9 expression is not obligatory for monocyte-macrophage maturation in AML-M5 cells carrying t(9;11)(p22;q23). In this study, we analyzed the expression patterns of HOXA4, 5, 6, 7, 9, 10 and 11 (defined as 'HOXA-code' genes) and MEIS1 by semiquantitative RT-PCR during the monocyte-macrophage differentiation induced by phorbol 12-myristate 13-acetate (PMA) in THP-1 cells carrying t(9;11)(p22;q23) and expressing MLL-AF9. The analyses were performed in THP-1 cells expressing MLL-AF9 even after PMA treatment. The results showed that all the analyzed genes were expressed in untreated THP-1 cells. After the induction of differentiation, we observed a down-regulation of HOXA4, 7, 10, 11 and MEIS1, an up-regulation of HOXA6, and no significant variation in the expression of HOXA5 and 9. These data indicate that the expression of most HOXA-code genes, as well as MEIS1, could be implicated in the differentiation blockage observed in MLL-AF9-related leukemias.