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ACUTE LYMPHOBLASTIC LEUKEMIA

T-ALL can evolve to oncogene independence

Leukemia volume 35, pages 2205–2219 (2021)Cite this article

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Abstract

The majority of cases of T-cell acute lymphoblastic leukemia (T-ALL) contain chromosomal abnormalities that drive overexpression of oncogenic transcription factors. However, whether these initiating oncogenes are required for leukemia maintenance is poorly understood. To address this, we developed a tetracycline-regulated mouse model of T-ALL driven by the oncogenic transcription factor Lmo2. This revealed that whilst thymus-resident pre-Leukemic Stem Cells (pre-LSCs) required continuous Lmo2 expression, the majority of leukemias relapsed despite Lmo2 withdrawal. Relapse was associated with a mature phenotype and frequent mutation or loss of tumor suppressor genes including Ikzf1 (Ikaros), with targeted deletion Ikzf1 being sufficient to transform Lmo2-dependent leukemias to Lmo2-independence. Moreover, we found that the related transcription factor TAL1 was dispensable in several human T-ALL cell lines that contain SIL-TAL1 chromosomal deletions driving its overexpression, indicating that evolution to oncogene independence can also occur in human T-ALL. Together these results indicate an evolution of oncogene addiction in murine and human T-ALL and show that loss of Ikaros is a mechanism that can promote self-renewal of T-ALL lymphoblasts in the absence of an initiating oncogenic transcription factor.

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Fig. 1: A regulatable model of Lmo2-driven T-cell leukemogenesis.
Fig. 2: Silencing Lmo2 expression overcomes the Lmo2-induced T-cell developmental block.
Fig. 3: Silencing Lmo2 expression eliminates self-renewing pre-LSCs.
Fig. 4: Lmo2 induces Lmo2-dependent, Evolving and Lmo2-independent T-ALL.
Fig. 5: Lmo2-dependence is associated with an immature (ETP-like) gene expression profile.
Fig. 6: Genomic analysis of Lmo2-dependent, evolving, and Lmo2-independent leukemias.
Fig. 7: Ikzf1 loss promotes evolution to Lmo2-independence.
Fig. 8: Deletion of TAL1 is tolerated in several human T-ALL cell lines.

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Acknowledgements

The authors thank Alfred Medical Research and Education Precinct (AMREP) animal services and Walter and Eliza Hall Institute (WEHI) Bioservices and for mouse husbandry, Fiona Waters and the WEHI Central Microinjection Service for transgenic mouse generation and the AMREP and WEHI Flow Cytometry Facilities. We thank Cedric Tremblay for antibodies and discussions and Helen Mitchell and Wei Shi for assistance with RNA sequencing and bioinformatics. We thank Charles de Bock, Chris Riffkin, David Huang and Sandra Mifsud for cell lines. This work was supported by project grants (1003391 and 1104145 to MPM), a Program grant (1113577 to WSA), a Fellowship (1058344 to WSA), and the Independent Research Institute’s Infrastructure Support Scheme from the Australian Government’s National Health and Medical Research Council (NHMRC), the Fund for Scientific Research Flanders (LD and PVV), the Ghent University Research Fund and the European Research Council (StG-639784 to PVV), a grant-in-aid from the Cancer Council of Victoria, a Future Fellowship from the Australian Research Council (MPM) and a Victorian State Government Operational Infrastructure Support grant.

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  1. These authors contributed equally: Hesham Abdulla, Anh Vo, Benjamin J. Shields, Tenae J. Davies

Authors and Affiliations

  1. Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia

    Hesham Abdulla, Jacob T. Jackson, Raed Alserihi, Elizabeth M. Viney & Warren S. Alexander

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

    Anh Vo, Benjamin J. Shields, Tenae J. Davies, Jacob T. Jackson, Tin Wong, Feng Yan, Nicholas C. Wong, David J. Curtis, Ross A. Dickins & Matthew P. McCormack

  3. College of Applied Medical Sciences, King Abdul-Aziz University, Jeddah, Saudi Arabia

    Raed Alserihi

  4. Monash Bioinformatics Platform, Monash University, Melbourne, VIC, Australia

    Feng Yan & Nicholas C. Wong

  5. Department of Biomolecular Medicine, Ghent University, Ghent, Belgium

    Lisa Demoen & Pieter Van Vlierberghe

  6. Cancer Research Institute Ghent (CRIG), Ghent, Belgium

    Lisa Demoen & Pieter Van Vlierberghe

  7. Department of Medical Biology, The University of Melbourne, Parkville, VIC, Australia

    Warren S. Alexander

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Abdulla, H., Vo, A., Shields, B.J. et al. T-ALL can evolve to oncogene independence. Leukemia 35, 2205–2219 (2021). https://doi.org/10.1038/s41375-021-01120-9

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