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

J Exp Med, 2013/7/29;210(8):1545-57.

Mansour MR[1], Sanda T, Lawton LN, Li X, Kreslavsky T, Novina CD, Brand M, Gutierrez A, Kelliher MA, Jamieson CH, von Boehmer H, Young RA, Look AT

Affiliations

PMID: 23857984DOI: 10.1084/jem.20122516

Impact factor: 17.579

Abstract
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.
MeSH terms
3' Untranslated Regions; Animals; Apoptosis; Basic Helix-Loop-Helix Transcription Factors; Cell Cycle Proteins; F-Box Proteins; F-Box-WD Repeat-Containing Protein 7; Gene Expression Profiling; Gene Expression Regulation, Leukemic; Gene Knockdown Techniques; Humans; Mice; MicroRNAs; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma; Proto-Oncogene Proteins; T-Cell Acute Lymphocytic Leukemia Protein 1; Thymus Gland; Transcriptional Activation; Ubiquitin-Protein Ligases
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