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PML targeting eradicates quiescent leukaemia-initiating cells

Nature volume 453, pages 1072–1078 (2008)Cite this article

Abstract

The existence of a small population of ‘cancer-initiating cells’ responsible for tumour maintenance has been firmly demonstrated in leukaemia. This concept is currently being tested in solid tumours. Leukaemia-initiating cells, particularly those that are in a quiescent state, are thought to be resistant to chemotherapy and targeted therapies, resulting in disease relapse. Chronic myeloid leukaemia is a paradigmatic haematopoietic stem cell disease in which the leukaemia-initiating-cell pool is not eradicated by current therapy, leading to disease relapse on drug discontinuation. Here we define the critical role of the promyelocytic leukaemia protein (PML) tumour suppressor in haematopoietic stem cell maintenance, and present a new therapeutic approach for targeting quiescent leukaemia-initiating cells and possibly cancer-initiating cells by pharmacological inhibition of PML.

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Figure 1: PML is highly expressed in HSCs and CML.
Figure 2: Pml is essential for HSC maintenance.
Figure 3: Pml is essential for LIC maintenance.
Figure 4: Reduction of Pml by As 2 O 3 treatment abrogates maintenance of HSC quiescence.
Figure 5: Combination therapy with Ara-C and As 2 O 3 eliminates LICs.

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Acknowledgements

We thank S. Ogilvie for analysis of patient samples and data management, and all members of the Pandolfi laboratory for comments and discussion. K.I. was supported by a JSPS postdoctoral fellowship for research abroad. R.B. is supported by a K01 NIH grant. This work was supported by NIH grants to P.P.P.

Author Contributions The experiments were conceived and designed by K.I., R.B., A.M. and P.P.P. Experiments were performed by K.I., R.B. and A.M. Immunohistochemistry of patient samples was conducted and investigated by J.T.-F, K.I. and R.B. Experiments on primary human CML samples were performed by A.M., S.M., G.S., Y.I., J.R., K.I. and D.E.A. Data were analysed by K.I., R.B., A.M. and P.P.P. The paper was written by K.I., R.B., A.M. and P.P.P.

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Authors and Affiliations

  1. Departments of Medicine and Pathology,, Cancer Genetics Program, Beth Israel Deaconess Cancer Center,

    Keisuke Ito, Rosa Bernardi, Alessandro Morotti & Pier Paolo Pandolfi

  2. Division of Hematology and Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School, New Research Building, 330 Brookline Avenue, Boston, Massachusetts 02215, USA,

    Jacalyn Rosenblatt & David E. Avigan

  3. Cancer Biology and Genetics Program,,

    Keisuke Ito, Rosa Bernardi, Alessandro Morotti & Pier Paolo Pandolfi

  4. Department of Pathology, Memorial Sloan-Kettering Cancer Center, Sloan-Kettering Institute, 1275 York Avenue, New York, New York 10021, USA,

    Keisuke Ito, Rosa Bernardi, Alessandro Morotti, Julie Teruya-Feldstein & Pier Paolo Pandolfi

  5. Division of Hematology, Department of Internal Medicine, Keio University School of Medicine, 35 Shinano-machi, Shinjuku-ku, Tokyo 160-8582, Japan,

    Sahoko Matsuoka & Yasuo Ikeda

  6. Division of Hematology and Internal Medicine, Department of Clinical and Biological Sciences, University of Turin, Turin 10043, Italy

    Giuseppe Saglio

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  1. Keisuke Ito
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Correspondence to Pier Paolo Pandolfi.

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Ito, K., Bernardi, R., Morotti, A. et al. PML targeting eradicates quiescent leukaemia-initiating cells. Nature 453, 1072–1078 (2008). https://doi.org/10.1038/nature07016

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