Regulation of the adaptor molecule LAT2, an in vivo target gene of AML1/ETO (RUNX1/RUNX1T1), during myeloid differentiation.

ABSTRACT

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.