RESUMEN
The leukaemia-specific fusion oncoprotein RUNX1/RUNX1T1 (AML1/ETO), resulting from the chromosomal translocation (8;21) in acute myeloid leukaemia (AML), imposes a striking genotype-phenotype relationship upon this distinct subtype of AML, which is mediated by multiple, co-ordinate downstream effects induced by this chimeric transcription factor. We previously identified the LAT2 gene, encoding the adaptor molecule LAT2 (NTAL, LAB), which is phosphorylated by KIT and has a role in mast cell and B-cell activation, as a target of the repressor activity of RUNX1/RUNX1T1. These results were confirmed and extended by demonstrating downregulation of the LAT2 protein in response to conditional RUNX1/RUNX1T1 expression, and its absence in primary AML with the t(8;21). In contrast, in a cohort of 43 AML patients, higher levels of LAT2 were associated with myelomonocytic features. Differentiation of HL-60 and NB4 cells towards granulocytes by all trans-retinoic acid (ATRA) resulted in downregulation of LAT2; conversely, it was upregulated during phorbol ester-induced monocytic differentiation of HL-60 cells. Forced expression of LAT2 in Kasumi-1 cells resulted in a striking block of ATRA- and phorbol ester-induced differentiation, implicating disturbances of the graded expression of this adaptor molecule in the maturation block of myeloid leukaemia cells.
Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/biosíntesis , Subunidad alfa 2 del Factor de Unión al Sitio Principal/fisiología , Leucemia Mieloide Aguda/metabolismo , Proteínas de Fusión Oncogénica/fisiología , Proteínas Adaptadoras Transductoras de Señales/genética , Adulto , Anciano , Anciano de 80 o más Años , Diferenciación Celular/efectos de los fármacos , Colecalciferol/farmacología , Cromosomas Humanos Par 21/genética , Cromosomas Humanos Par 8/genética , Regulación hacia Abajo/efectos de los fármacos , Femenino , Regulación Neoplásica de la Expresión Génica , Granulocitos/metabolismo , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patología , Macrófagos/metabolismo , Masculino , Persona de Mediana Edad , Monocitos/metabolismo , Proteínas de Neoplasias/biosíntesis , Proteínas de Neoplasias/genética , Ésteres del Forbol/farmacología , Proteína 1 Compañera de Translocación de RUNX1 , Translocación Genética , Células Tumorales Cultivadas , Regulación hacia Arriba/efectos de los fármacosRESUMEN
The adaptor protein linker activator of T-cells 2 (LAT2) is a known AML1/ETO target gene whose function during normal hematopoiesis is unknown. We addressed the role of LAT2 during erythroid and myeloid differentiation of normal human CD34+ hematopoietic cells. LAT2 is expressed at low levels in CD34+ cells and upregulated during cytokine-induced myeloid and erythroid differentiation. Forced LAT2 expression leads to a delay of erythroid and myeloid differentiation keeping CD34+ cells in a more immature state, whereas LAT2 knockdown accelerates differentiation. It is tempting to speculate that by affecting the differentiation capacity of normal hematopoietic progenitors, LAT2 may contribute to the pathogenesis of AML.