Mansour, Marc R.Sanda, TakaomiLawton, Lee N.Li, XiaoyuKreslavsky, TarasNovina, CarlBrand, MarjorieGutierrez, AlejandroKelliher, Michelle A.Jamieson, Catriona H.M.von Boehmer, HaraldYoung, Richard A.Look, A.2014-03-112013Mansour, M. R., T. Sanda, L. N. Lawton, X. Li, T. Kreslavsky, C. D. Novina, M. Brand, et al. 2013. “The TAL1 complex targets the FBXW7 tumor suppressor by activating miR-223 in human T cell acute lymphoblastic leukemia.” The Journal of Experimental Medicine 210 (8): 1545-1557. doi:10.1084/jem.20122516. http://dx.doi.org/10.1084/jem.20122516.0022-1007http://nrs.harvard.edu/urn-3:HUL.InstRepos:11879636The oncogenic transcription factor TAL1/SCL is aberrantly expressed in 60% of cases of human T cell acute lymphoblastic leukemia (T-ALL) and initiates T-ALL in mouse models. By performing global microRNA (miRNA) expression profiling after depletion of TAL1, together with genome-wide analysis of TAL1 occupancy by chromatin immunoprecipitation coupled to massively parallel DNA sequencing, we identified the miRNA genes directly controlled by TAL1 and its regulatory partners HEB, E2A, LMO1/2, GATA3, and RUNX1. The most dynamically regulated miRNA was miR-223, which is bound at its promoter and up-regulated by the TAL1 complex. miR-223 expression mirrors TAL1 levels during thymic development, with high expression in early thymocytes and marked down-regulation after the double-negative-2 stage of maturation. We demonstrate that aberrant miR-223 up-regulation by TAL1 is important for optimal growth of TAL1-positive T-ALL cells and that sustained expression of miR-223 partially rescues T-ALL cells after TAL1 knockdown. Overexpression of miR-223 also leads to marked down-regulation of FBXW7 protein expression, whereas knockdown of TAL1 leads to up-regulation of FBXW7 protein levels, with a marked reduction of its substrates MYC, MYB, NOTCH1, and CYCLIN E. We conclude that TAL1-mediated up-regulation of miR-223 promotes the malignant phenotype in T-ALL through repression of the FBXW7 tumor suppressor.en-USJournal Article2014-03-1110.1084/jem.20122516