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Acute lymphoblastic leukemia

The NUP98-HOXD13 fusion oncogene induces thymocyte self-renewal via Lmo2/Lyl1

Leukemia (2019) | Download Citation

Abstract

T cell acute lymphoblastic leukaemia (T-ALL) cases include subfamilies that overexpress the TAL1/LMO, TLX1/3 and HOXA transcription factor oncogenes. While it has been shown that TAL1/LMO transcription factors induce self-renewal of thymocytes, whether this is true for other transcription factor oncogenes is unknown. To address this, we have studied NUP98-HOXD13-transgenic (NHD13-Tg) mice, which overexpress HOXA transcription factors throughout haematopoiesis and develop both myelodysplastic syndrome (MDS) progressing to acute myeloid leukaemia (AML) as well as T-ALL. We find that thymocytes from preleukaemic NHD13-Tg mice can serially transplant, demonstrating that they have self-renewal capacity. Transcriptome analysis shows that NHD13-Tg thymocytes exhibit a stem cell-like transcriptional programme closely resembling that induced by Lmo2, including Lmo2 itself and its critical cofactor Lyl1. To determine whether Lmo2/Lyl1 are required for NHD13-induced thymocyte self-renewal, NHD13-Tg mice were crossed with Lyl1 knockout mice. This showed that Lyl1 is essential for expression of the stem cell-like gene expression programme in thymocytes and self-renewal. Surprisingly however, NHD13 transgenic mice lacking Lyl1 showed accelerated T-ALL and absence of transformation to AML, associated with a loss of multipotent progenitors in the bone marrow. Thus multiple T cell oncogenes induce thymocyte self-renewal via Lmo2/Lyl1; however, NHD13 can also promote T-ALL via an alternative pathway.

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Acknowledgements

The authors thank the Walter and Eliza Hall Institute (WEHI) Bioservices and Alfred Medical Research and Education Precinct (AMREP) animal services for mouse husbandry and the WEHI and AMREP Flow Cytometry Facilities. This work was supported by project grant (1031654 [to MPM, DJC] and 1104145 [to MPM]), a Senior Research Fellowship (to DJC) and the Independent Research Institute’s Infrastructure Support Scheme from the Australian Government’s National Health and Medical Research Council, grants-in-aid from the Cancer Council of Victoria (to MPM) and the Leukaemia Foundation of Australia (to MPM and CIS), a Future Fellowship from the Australian Research Council (to MPM) and a Victorian State Government Operational Infrastructure Support grant.

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Affiliations

  1. Australian Centre for Blood Diseases, Monash University, Melbourne, VIC, Australia

    • Benjamin J. Shields
    • , Ngoc Vo
    • , Jacob T. Jackson
    • , David J. Curtis
    •  & Matthew P. McCormack
  2. University of Queensland, Diamantina Institute, Brisbane, VIC, Australia

    • Christopher I. Slape
    • , Adriana Pliego-Zamora
    •  & Hansini Ranasinghe
  3. The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, 3052, Australia

    • Wei Shi
  4. Department of Computing and Information Systems, The University of Melbourne, Parkville, VIC, 3010, Australia

    • Wei Shi
  5. Clinical Haematology, Alfred Hospital, Melbourne, VIC, Australia

    • David J. Curtis

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The authors declare that they have no conflict of interest.

Corresponding author

Correspondence to Matthew P. McCormack.

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DOI

https://doi.org/10.1038/s41375-018-0361-0