Journal
JOURNAL OF EXPERIMENTAL MEDICINE
Volume 210, Issue 8, Pages 1545-1557Publisher
ROCKEFELLER UNIV PRESS
DOI: 10.1084/jem.20122516
Keywords
-
Categories
Funding
- Kay Kendall Leukaemia Fund of the UK
- Team Path To the Cure grant
- National Cancer Institute [5P01CA109901, 5P01CA68484, 1K99CA157951]
- National Institutes of Health (NIH), National Cancer Institute, Center for Cancer Research
- William Lawrence and Blanche Hughes Foundation
- Children's Leukemia Research Association
- Japan Society for the Promotion of Science
- NIH [1K08CA133103]
Ask authors/readers for more resources
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.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available