Details

Autor(en) / Beteiligte

• Mansour, Marc R
• Sanda, Takaomi
• Lawton, Lee N
• Li, Xiaoyu
• Kreslavsky, Taras
• Novina, Carl D
• Brand, Marjorie
• Gutierrez, Alejandro
• Kelliher, Michelle A
• Jamieson, Catriona H M
• von Boehmer, Harald
• Young, Richard A
• Look, A Thomas

Titel

The TAL1 complex targets the FBXW7 tumor suppressor by activating miR-223 in human T cell acute lymphoblastic leukemia

Ist Teil von

• The Journal of experimental medicine, 2013-07, Vol.210 (8), p.1545-1557

Ort / Verlag

United States: The Rockefeller University Press

Erscheinungsjahr

2013

Quelle

MEDLINE

Beschreibungen/Notizen

• The 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.