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Molecular Targets for Therapy

Both leukaemic and normal peripheral B lymphoid cells are highly sensitive to the selective pharmacological inhibition of prosurvival Bcl-2 with ABT-199

Leukemia volume 28, pages 1207–1215 (2014)Cite this article

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Abstract

Overexpression of the prosurvival protein Bcl-2 marks many B-lymphoid malignancies and contributes to resistance to many commonly used chemotherapeutic agents. The first effective BH3 mimetic inhibitors of Bcl-2, ABT-737 and navitoclax, also target Bcl-xL, causing dose-limiting thrombocytopenia. This prompted the development of the Bcl-2-selective antagonist, ABT-199. Here we show that in lymphoid cells, ABT-199 specifically causes Bax/Bak-mediated apoptosis that is triggered principally by the initiator BH3-only protein Bim. As expected, malignant cells isolated from patients with chronic lymphocytic leukaemia are highly sensitive to ABT-199. However, we found that normal, untransformed mature B cells are also highly sensitive to ABT-199, both in vitro and in vivo. By contrast, the B-cell precursors are largely spared, as are cells of myeloid origin. These results pinpoint the probable impact of the pharmacological inhibition of Bcl-2 by ABT-199 on the normal mature haemopoietic cell lineages in patients, and have implications for monitoring during ABT-199 therapy as well as for the clinical utility of this very promising targeted agent.

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Acknowledgements

We thank our colleagues Andreas Strasser and Jerry Adams for helpful discussions. We thank Abbvie and Genentech for providing ABT-737, navitoclax (ABT-263) and ABT-199; Naomi Sprigg, Lisa Magee, Mary Moody, Lina Laskos and Jenni Harris for assistance with obtaining human samples; Louise Cengia, Angela Georgiou and Mikara Robati for technical assistance; Lorraine O’Reilly for antibodies; Bruno Helbert and Carley Young for mouse genotyping; and Emily Sutherland, Tania Camilleri, Anndrea Pomphrey and Giovanni Siciliano for mouse husbandry. This work was supported by fellowships and grants from the Australian National Health and Medical Research Council (Career Development Award to PB; Practitioner Fellowship to AWR; Research Fellowships to DCSH and PB; Program Grants 461219, 461221, 1051235 and 1016701; Independent Research Institutes Infrastructure Support Scheme grant 361646); the Leukemia and Lymphoma Society (SCOR grants 7417-07 and 7001-13); the Australian Research Council (Discovery Project to DM); the Leukaemia Foundation of Australia (Fellowship to SLK; Grants-in-Aid to SPG, AWR and DCSH); the Cancer Council of Victoria (Fellowship to SLK; Project Grant to AWR and DCSH); Australian Cancer Research Foundation; and a Victorian State Government Operational Infrastructure Support (OIS) Grant.

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Author notes

  1. S L Khaw and D Mérino: These authors contributed equally to this work.

Authors and Affiliations

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

    S L Khaw, D Mérino, M A Anderson, S P Glaser, P Bouillet, A W Roberts & D C S Huang

  2. Department of Medical Biology, University of Melbourne, Parkville, VIC, Australia

    S L Khaw, D Mérino, M A Anderson, S P Glaser, P Bouillet, A W Roberts & D C S Huang

  3. Royal Children’s Hospital, Parkville, VIC, Australia

    S L Khaw

  4. Department of Clinical Haematology and BMT, Royal Melbourne Hospital, Parkville, VIC, Australia

    M A Anderson & A W Roberts

  5. Department of Medicine, Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Parkville, VIC, Australia

    M A Anderson & A W Roberts

  6. Victorian Comprehensive Cancer Centre, Parkville, VIC, Australia

    A W Roberts

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  1. S L Khaw
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Correspondence to D C S Huang.

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SLK, DM, PB, AWR and DCSH are employees of the Walter and Eliza Hall Institute, which receives commercial income and has received research funding from Genentech and Abbott Laboratories (now Abbvie). The remaining authors declare no conflict of interest.

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Khaw, S., Mérino, D., Anderson, M. et al. Both leukaemic and normal peripheral B lymphoid cells are highly sensitive to the selective pharmacological inhibition of prosurvival Bcl-2 with ABT-199. Leukemia 28, 1207–1215 (2014). https://doi.org/10.1038/leu.2014.1

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