TRIB2 reinforces the oncogenic transcriptional program controlled by the TAL1 complex in T-cell acute lymphoblastic leukemia

• Main Authors: Tan, S H (Author), Yam, A W Y (Author), Lawton, L N (Author), Wong, R W J (Author), Young, R A (Author), Look, A T (Author), Sanda, T (Author), Young, Richard A. (Author)
• Other Authors: Massachusetts Institute of Technology. Department of Biology (Contributor), Whitehead Institute for Biomedical Research (Contributor), Young, Richard A (Contributor)
• Format: Article
• Language: English
• Published: Nature Publishing Group, 2017-02-10T16:09:48Z.
• Subjects: Article
• Online Access: Get fulltext

T-cell acute lymphoblastic leukemia (T-ALL) is a malignant disorder resulting from the leukemic transformation of T-cell precursors, and is one of the most common forms of cancer in children and is also found in adults. The most frequent genetic abnormality in T-ALL is the dysregulation of transcription factor genes, including aberrant expression of TAL1/SCL. TAL1 is ectopically expressed in 40-60% of T-ALL cases owing to chromosomal translocation, intrachromosomal rearrangement ('SIL-TAL deletion') or a somatic mutation in a non-coding intergenic element. We previously reported that TAL1 forms a positive interconnected autoregulatory loop with its regulatory partners GATA3, RUNX1 and MYB ('core regulatory circuits'). To identify critical downstream targets that contribute to T-cell leukemogenesis, we have also performed a loss-of-function RNA interference screen in the TAL1-positive T-ALL cell lines in our previous study.6 Among the high-confidence TAL1 targets, only four genes, including the Tribbles homolog 2 (TRIB2), were selected by this screen. TRIB2 is a pseudo-kinase protein and has been implicated as an oncogene that contributes to acute myeloid leukemia (AML) by negatively regulating the C/EBPα tumor suppressor protein. TRIB2 is also a transcriptional target of the oncogene NOTCH1 in T-ALL. However, the oncogenic role of TRIB2 in T-ALL pathogenesis, in particular, as a downstream consequence of the core regulatory circuits, has not been elucidated. In this study, we identified molecular pathways regulated by TRIB2 in T-ALL cells.
National Cancer Institute (U.S.) (Grants 1K99CA157951 and 5P01CA109901)
Singapore. National Research Foundation. Competitive Research Programme (Award NRF-NRFF2013-02)