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

Leukemia volume 30, pages 959–962 (2016)Cite this article

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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.1, 2, 3 The most frequent genetic abnormality in T-ALL is the dysregulation of transcription factor genes, including aberrant expression of TAL1/SCL.1, 2, 3 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.1, 3, 4, 5 We previously reported that TAL1 forms a positive interconnected autoregulatory loop with its regulatory partners GATA3, RUNX1 and MYB (‘core regulatory circuits’).3, 6 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.7, 8 TRIB2 is also a transcriptional target of the oncogene NOTCH1 in T-ALL.9 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.

We next examined the mechanism of regulation of the TAL1 targets by TRIB2. Analysis of mRNA expression revealed that four major components of the TAL1 complex, namely TAL1, GATA3, RUNX1 and MYB, were downregulated after TRIB2 knockdown in Jurkat cells (Supplementary Figure 2b). This trend was more significant at the protein level in the same cell line (Figure 2b, left), presumably owing to a high protein turnover of these factors. The similar result was observed with an independent shRNA targeting TRIB2 (Supplementary Figure 1e). We previously reported that these genes positively regulate each other through an autoregulatory loop in this cell line.4, 6 Indeed, overexpression of TRIB2 upregulated expression of all of these proteins in the same cell line both at the mRNA (Supplementary Figure 2c) and protein levels (Supplementary Figure 2d). Notably, TAL1 was not downregulated after TRIB2 knockdown in two TAL1-positive cell lines (RPMI-8402 and CCRF-CEM; Figure 2b) where TAL1 is driven by the SIL gene promoter, which is activated independently of the TAL1 complex.12 In addition, downregulation of GATA3, RUNX1 and MYB was not significant in the TAL1-negative cell lines (Figure 2b). Although additional study is needed to clarify the mechanism of regulation of the TAL1 complex by TRIB2, these results suggest that TRIB2 upregulates the expression of the TAL1 complex members by affecting the positive autoregulatory loop. Importantly, the decrease in protein expression of these transcription factors was also observed after TRIB2 knockdown in the XIAP- or BCL2-overexpressing cells (Supplementary Figures 2e and f) where apoptosis was blocked (Supplementary Figure 1g; and see PARP cleavage in Supplementary Figures 2e and 2f), demonstrating that the regulation of transcription factor proteins is not a result of cell death.

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Acknowledgements

We thank members of the Sanda and Look laboratories for discussions. We thank the Nature Publishing Group Language Editing group for editing the manuscript. This research is supported by the US National Cancer Institute (1K99CA157951 and 5P01CA109901) and the National Research Foundation, Prime Minister’s Office, Singapore under its Competitive Research Programme (Award No. NRF-NRFF2013-02).

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Authors and Affiliations

  1. Cancer Science Institute of Singapore, National University of Singapore, Singapore

    S H Tan, A W Y Yam, R W J Wong & T Sanda

  2. Whitehead Institute for Biomedical Research, Cambridge, MA, USA

    L N Lawton & R A Young

  3. Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA

    R A Young

  4. Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA

    A T Look

  5. Division of Hematology/Oncology, Children's Hospital, Boston, MA, USA

    A T Look

  6. Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore

    T Sanda

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Tan, S., Yam, A., Lawton, L. et al. TRIB2 reinforces the oncogenic transcriptional program controlled by the TAL1 complex in T-cell acute lymphoblastic leukemia. Leukemia 30, 959–962 (2016). https://doi.org/10.1038/leu.2015.195

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