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Differentiation

ATRA and the specific RARα agonist, NRX195183, have opposing effects on the clonogenicity of pre-leukemic murine AML1-ETO bone marrow cells

Leukemia volume 27, pages 1369–1380 (2013)Cite this article

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Abstract

All-trans retinoic acid (ATRA) is used successfully in the treatment of acute promyelocytic leukemia (APL). ATRA enhances hematopoietic stem cell self-renewal through retinoic acid receptor (RAR)γ activation while promoting differentiation of committed myeloid progenitors through RARα activation. Its lack of success in the treatment of non-APL acute myeloid leukemia (AML) may be related to ATRA’s non-selectivity for the RARα and RARγ isotypes, and specific RARα activation may be more beneficial in promoting myeloid differentiation. To investigate this hypothesis, the effects of ATRA and the specific RARα agonist NRX195183 was assessed in AML1-ETO (AE)-expressing murine bone marrow (BM) progenitors. ATRA potentiated the in vitro clonogenicity of these cells while NRX195183 had the opposite effect. Morphological and flow cytometric analysis confirmed a predominantly immature myeloid population in the ATRA-treated AE cells while the NRX195183-treated cells demonstrated an increase in the mature myeloid population. Similarly, NRX195183 treatment promoted myeloid differentiation in an AE9a in vivo murine model. In the ATRA-treated AE cells, gene expression analyses revealed functional networks involving SERPINE1 and bone morphogenetic protein 2; AKT phosphorylation was upregulated. Collectively, these findings confirm the contrasting roles of specific RARα and RARγ activation in the clonogenicity and differentiation of AE cells with potential significant implications in the treatment of non-APL AML using a specific RARα agonist.

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Acknowledgements

This work was supported in part by grants from the National Health and Medical Research Council (NHMRC, Canberra, Australia) Project Grant 350272 (GAM and LEP), NHMRC Practitioner Fellowship (GAM) and CSL Limited (Victoria, Australia) (LCYC). LCYC is also a recipient of a University of Melbourne Faculty of Medicine, Dentistry and Health Sciences Research Scholarship and a Royal Australasian College of Physicians Arnott Research Entry Scholarship for Cancer Research. LEP is an NHMRC Senior Research Fellow. GAM was a recipient of a Cancer Council of Victoria Sir Edward Weary Dunlop Clinical Research Fellowship. Many thanks to Prof. James R Downing (St. Jude Children’s Research Hospital, Memphis, TN, USA) for provision of the AML1-ETO-stop/+ mice, Dr David Curtis (Rotary Bone Marrow Research Laboratories, The Royal Melbourne Hospital, Melbourne, Victoria, Australia) for provision of the Mx1-Cre+ mice, Dr David Izon (St. Vincent’s Institute, Fitzroy, Victoria, Australia) for provision of the MigR1 vector, Dr Carleen Cullinane and the Translational Research Laboratory staff for technical assistance with mice procedures, Rebecca Driessen from the Microarray Core for processing of RNA samples, Jason Ellul from the Bioinformatics Department for assistance with analysis, Dr Rosh Chandraratna from IO Therapeutics for helpful discussions and the PMCC Animal Facility staff for care of experimental mice.

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Authors and Affiliations

  1. Research Division, Molecular Oncology Laboratory, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia

    L C Y Chee, J Hendy & G A McArthur

  2. Department of Medicine, St Vincent’s Hospital, University of Melbourne, Fitzroy, Victoria, Australia

    L C Y Chee, L E Purton & G A McArthur

  3. Department of Clinical Haematology and Bone Marrow Transplant Unit, Royal Melbourne Hospital, Parkville, Victoria, Australia

    L C Y Chee

  4. Stem Cell Regulation Unit, St Vincent’s Institute, Fitzroy, Victoria, Australia

    J Hendy & L E Purton

  5. Division of Cancer Medicine, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia

    G A McArthur

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  1. L C Y Chee
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Correspondence to G A McArthur.

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LCYC designed and performed research, collected data, analyzed and interpreted data, performed statistical analysis and wrote the manuscript; JH designed and performed research, and collected data; and LEP and GAM designed the research, interpreted data and wrote the manuscript.

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Chee, L., Hendy, J., Purton, L. et al. ATRA and the specific RARα agonist, NRX195183, have opposing effects on the clonogenicity of pre-leukemic murine AML1-ETO bone marrow cells. Leukemia 27, 1369–1380 (2013). https://doi.org/10.1038/leu.2012.362

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