title: 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.
authors.affiliation: Department of Haematology/Oncology, University of Freiburg, Hugstetter Strasse 55, Freiburg, Germany.
authors.forename: Jesús
authors.initials: J
authors.lastname: Duque-Afonso
authors.forename: Leticia
authors.initials: L
authors.lastname: Solari
authors.forename: Aitomi
authors.initials: A
authors.lastname: Essig
authors.forename: Tobias
authors.initials: T
authors.lastname: Berg
authors.forename: Heike L
authors.initials: HL
authors.lastname: Pahl
authors.forename: Michael
authors.initials: M
authors.lastname: Lübbert
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000096:biosynthesis* / Q000235:genetics; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002454:Cell Differentiation / Q000187:drug effects; D002762:Cholecalciferol / Q000494:pharmacology; D002891:Chromosomes, Human, Pair 21 / Q000235:genetics; D002898:Chromosomes, Human, Pair 8 / Q000235:genetics; D050676:Core Binding Factor Alpha 2 Subunit / Q000502:physiology*; D015536:Down-Regulation / Q000187:drug effects; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006098:Granulocytes / Q000378:metabolism; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008264:Macrophages / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000378:metabolism; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics; D015514:Oncogene Proteins, Fusion / Q000502:physiology*; D010703:Phorbol Esters / Q000494:pharmacology; D000075142:RUNX1 Translocation Partner 1 Protein; D014178:Translocation, Genetic; D014407:Tumor Cells, Cultured; D015854:Up-Regulation / Q000187:drug effects
chemical_list: C107844:AML1-ETO fusion protein, human; D048868:Adaptor Proteins, Signal Transducing; D050676:Core Binding Factor Alpha 2 Subunit; C419196:LAT2 protein, human; D009363:Neoplasm Proteins; D015514:Oncogene Proteins, Fusion; D010703:Phorbol Esters; D000075142:RUNX1 Translocation Partner 1 Protein; D002762:Cholecalciferol