TLX1/HOX11 encodes an NK-like homeodomain transcription factor that is both normally required for embryonic development and aberrantly expressed in T-cell acute lymphoblastic leukemia. Previous studies have shown that TLX1 can regulate target genes including ALDH1A1 and FHL1. However, whereas ALDH1A1 is consistently regulated by TLX1, endogenous FHL1 is only induced in a proportion of fibroblast or T-cell clones stably expressing TLX1. Here, we provide an explanation for these findings by demonstrating that the induction of FHL1, but not ALDH1A1, requires a high level of TLX1 expression in NIH 3T3 cells. In luciferase reporter assays, TLX1-mediated repression rather than activation of the FHL1 gene promoter and the magnitude of this effect was strongly influenced by the cellular background. Together, these results characterize TLX1 as a dual function regulator whose activity in respect to FHL1 is critically dependent upon its cellular concentration, as well as cell type and promoter context. (c) 2007 Elsevier Inc. All rights reserved.