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TRIB2 Reinforces the Oncogenic Transcriptional Program Controlled by the TAL1 Complex in T-cell Acute Lymphoblastic Leukemia. (Leukemia, Jul 2015)

Tan SH1, Yam AW1, Lawton LN2, Wong RW1, Young RA3, Look AT4, Sanda T5.

1 Cancer Science Institute of Singapore, National University of Singapore, Singapore.
2 Whitehead Institute for Biomedical Research, Cambridge, MA, USA.
3 Whitehead Institute for Biomedical Research, Cambridge, MA, USA; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA.
4 Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA; Division of Hematology/Oncology, Children’s Hospital, Boston, MA, USA.
5 Cancer Science Institute of Singapore, National University of Singapore, Singapore; Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.

Abstract:
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. 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.