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Acute myeloid leukemia

JMJD1C-mediated metabolic dysregulation contributes to HOXA9-dependent leukemogenesis

Leukemia volume 33, pages 1400–1410 (2019)Cite this article

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Abstract

Abnormal metabolism is a fundamental hallmark of cancer and represents a therapeutic opportunity, yet its regulation by oncogenes remains poorly understood. Here, we uncover that JMJD1C, a jumonji C (JmjC)-containing H3K9 demethylase, is a critical regulator of aberrant metabolic processes in homeobox A9 (HOXA9)-dependent acute myeloid leukemia (AML). JMJD1C overexpression increases in vivo cell proliferation and tumorigenicity through demethylase-independent upregulation of a glycolytic and oxidative program, which sustains leukemic cell bioenergetics and contributes to an aggressive AML phenotype in vivo. Targeting JMJD1C-mediated metabolism via pharmacologic inhibition of glycolysis and oxidative phosphorylation led to ATP depletion, induced necrosis/apoptosis and decreased tumor growth in vivo in leukemias co-expressing JMJD1C and HOXA9. The anti-metabolic therapy effectively diminished AML stem/progenitor cells and reduced tumor burden in a primary AML patient-derived xenograft. Our data establish a direct link between drug responses and endogenous expression of JMJD1C and HOXA9 in human AML cell line- and patient-derived xenografts. These findings demonstrate a previously unappreciated role for JMJD1C in counteracting adverse metabolic changes and retaining the metabolic integrity during tumorigenesis, which can be exploited therapeutically.

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Acknowledgments

We thank Bing Liu, Jin Yi Lim, Emma Ramsay, and the staff of the Mark Wainwright Analytical Centre for their assistance, and the CCI tumor bank for human AML samples. This work was supported by NHMRC APP1128824 and Cancer Council NSW RG15-11 (J.Y.W.).

Author contributions

J.R.L., B.S., P.C. and H.H.L.L. performed experiments; A.P. and P.H. partially contributed to bioenergetic analysis; B.V., I.J., K.S., T.T., T.L., M.H., M.D.N., A.J.W. and J.W. contributed to experimental reagents; J.Y.W. wrote the paper, managed the project, and supported the work.

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Author notes

  1. These authors contributed equally: Jennifer R. Lynch, Basit Salik

Authors and Affiliations

  1. Cancer and Stem Cell Biology Group, Children’s Cancer Institute, University of New South Wales, Sydney, NSW 2052, Australia

    Jennifer R. Lynch, Basit Salik, Patrick Connerty, Halina Leung & Jenny Y. Wang

  2. German Cancer Research Center (DKFZ), Heidelberg, Germany

    Binje Vick & Karsten Spiekermann

  3. German Cancer Consortium (DKTK), partner site Munich, Heidelberg, Germany

    Binje Vick, Irmela Jeremias & Karsten Spiekermann

  4. Research Unit Apoptosis in Hematopoietic Stem Cells, Helmholtz Zentrum München, German Research Center for Environmental Health, Munich, Germany

    Binje Vick & Irmela Jeremias

  5. The Centenary Institute, NHMRC Clinical Trials Centre, Sydney Medical School, University of Sydney, Camperdown, NSW 2006, Australia

    Aster Pijning & Philip Hogg

  6. Department of Pediatrics, Dr. von Hauner Childrens Hospital, Ludwig Maximilians University, Munich, Germany

    Irmela Jeremias

  7. Experimental Leukemia and Lymphoma Research Department of Internal Medicine 3, University Hospital, Ludwig-Maximilians-Universität München, Munich, Germany

    Karsten Spiekermann

  8. Children’s Cancer Institute, University of New South Wales, Sydney, NSW 2052, Australia

    Toby Trahair, Tao Liu, Michelle Haber & Murray D. Norris

  9. Centre for Childhood Cancer Research, Faculty of Medicine, University of New South Wales, Sydney, NSW 2052, Australia

    Tao Liu, Murray D. Norris & Jenny Y. Wang

  10. Harry Perkins Institute of Medical Research, QEII Medical Centre, Nedlands and Centre for Medical Research, The University of Western Australia, Crawley, WA 6009, Australia

    Andrew J. Woo

  11. Department of Cell, Developmental and Regenerative Biology, Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA

    Jianlong Wang

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  1. Jennifer R. Lynch
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Lynch, J.R., Salik, B., Connerty, P. et al. JMJD1C-mediated metabolic dysregulation contributes to HOXA9-dependent leukemogenesis. Leukemia 33, 1400–1410 (2019). https://doi.org/10.1038/s41375-018-0354-z

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