PML targeting eradicates quiescent leukaemia-initiating cells

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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Correspondence to Pier Paolo Pandolfi.

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The file contains Supplementary Figures 1-12 with Legends and Supplementary Tables 1-4. (PDF 2002 kb)

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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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