TY - JOUR
T1 - Targeting quiescent leukemic stem cells using second generation autophagy inhibitors
AU - Baquero, Pablo
AU - Dawson, Amy
AU - Mukhopadhyay, Arunima
AU - Kuntz, Elodie M.
AU - Mitchell, Rebecca
AU - Olivares, Orianne
AU - Ianniciello, Angela
AU - Scott, Mary T.
AU - Dunn, Karen
AU - Nicastri, Michael C.
AU - Winkler, Jeffrey D.
AU - Michie, Alison M.
AU - Ryan, Kevin M.
AU - Halsey, Christina
AU - Gottlieb, Eyal
AU - Keaney, Erin P.
AU - Murphy, Leon O.
AU - Amaravadi, Ravi K.
AU - Holyoake, Tessa L.
AU - Helgason, G. Vignir
N1 - Funding Information:
Acknowledgements We would like to dedicate this work to Prof. Tessa Holyoake. Tessa was a brilliant woman in every sense of the word and an inspiration to us all. We thank all patients and healthy donors who donated samples and National Health Service (NHS) Greater Glasgow and Clyde Biorepository; D. Vetrie for linguistic assistance; A. Hair for sample processing; Jennifer Cassels, T. Gilbey and T. Harvey for cell sorting and the Biological Services Unit from the Cancer Research UK Beatson Institute of Cancer Research for animal assistance. This study was supported by Cancer Research UK; the Cancer Research UK Glasgow Centre (C596/A18076) and the BSU facilities at the Cancer Research UK Beatson Institute (C596/ A17196); MRC/AstraZeneca project grants (MR/K014854/1); Kay Kendall Leukemia Fund (KKLF) (KKL501, KKL698 and KKL1069); Leuka; the Howat Foundation and Friends of Paul O’Gorman; the Bloodwise Specialist Programme (14033); and Lady Tata International Award. G.V.H. is a KKLF Intermediate Research Fellow, Leadership Fellow and John Goldman Fellow.
Publisher Copyright:
© 2018, Springer Nature Limited.
PY - 2019/4/1
Y1 - 2019/4/1
N2 - In chronic myeloid leukemia (CML), tyrosine kinase inhibitor (TKI) treatment induces autophagy that promotes survival and TKI-resistance in leukemic stem cells (LSCs). In clinical studies hydroxychloroquine (HCQ), the only clinically approved autophagy inhibitor, does not consistently inhibit autophagy in cancer patients, so more potent autophagy inhibitors are needed. We generated a murine model of CML in which autophagic flux can be measured in bone marrow-located LSCs. In parallel, we use cell division tracing, phenotyping of primary CML cells, and a robust xenotransplantation model of human CML, to investigate the effect of Lys05, a highly potent lysosomotropic agent, and PIK-III, a selective inhibitor of VPS34, on the survival and function of LSCs. We demonstrate that long-term haematopoietic stem cells (LT-HSCs: Lin − Sca-1 + c-kit + CD48 − CD150 + ) isolated from leukemic mice have higher basal autophagy levels compared with non-leukemic LT-HSCs and more mature leukemic cells. Additionally, we present that while HCQ is ineffective, Lys05-mediated autophagy inhibition reduces LSCs quiescence and drives myeloid cell expansion. Furthermore, Lys05 and PIK-III reduced the number of primary CML LSCs and target xenografted LSCs when used in combination with TKI treatment, providing a strong rationale for clinical use of second generation autophagy inhibitors as a novel treatment for CML patients with LSC persistence.
AB - In chronic myeloid leukemia (CML), tyrosine kinase inhibitor (TKI) treatment induces autophagy that promotes survival and TKI-resistance in leukemic stem cells (LSCs). In clinical studies hydroxychloroquine (HCQ), the only clinically approved autophagy inhibitor, does not consistently inhibit autophagy in cancer patients, so more potent autophagy inhibitors are needed. We generated a murine model of CML in which autophagic flux can be measured in bone marrow-located LSCs. In parallel, we use cell division tracing, phenotyping of primary CML cells, and a robust xenotransplantation model of human CML, to investigate the effect of Lys05, a highly potent lysosomotropic agent, and PIK-III, a selective inhibitor of VPS34, on the survival and function of LSCs. We demonstrate that long-term haematopoietic stem cells (LT-HSCs: Lin − Sca-1 + c-kit + CD48 − CD150 + ) isolated from leukemic mice have higher basal autophagy levels compared with non-leukemic LT-HSCs and more mature leukemic cells. Additionally, we present that while HCQ is ineffective, Lys05-mediated autophagy inhibition reduces LSCs quiescence and drives myeloid cell expansion. Furthermore, Lys05 and PIK-III reduced the number of primary CML LSCs and target xenografted LSCs when used in combination with TKI treatment, providing a strong rationale for clinical use of second generation autophagy inhibitors as a novel treatment for CML patients with LSC persistence.
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U2 - 10.1038/s41375-018-0252-4
DO - 10.1038/s41375-018-0252-4
M3 - Article
C2 - 30185934
AN - SCOPUS:85053056819
SN - 0887-6924
VL - 33
SP - 981
EP - 994
JO - Leukemia
JF - Leukemia
IS - 4
ER -