Inhibition of Pol I transcription treats murine and human AML by targeting the leukemia-initiating cell population

Author:

Hein Nadine12,Cameron Donald P.123ORCID,Hannan Katherine M.124ORCID,Nguyen Nhu-Y N.5,Fong Chun Yew236,Sornkom Jirawas23,Wall Meaghan78,Pavy Megan1,Cullinane Carleen23,Diesch Jeannine2,Devlin Jennifer R.2,George Amee J.1910ORCID,Sanij Elaine239,Quin Jaclyn2,Poortinga Gretchen239,Verbrugge Inge11,Baker Adele2,Drygin Denis12,Harrison Simon J.36ORCID,Rozario James D.13ORCID,Powell Jason A.1415,Pitson Stuart M.1415ORCID,Zuber Johannes16ORCID,Johnstone Ricky W.239,Dawson Mark A.236ORCID,Guthridge Mark A.5,Wei Andrew517,McArthur Grant A.236,Pearson Richard B.23418,Hannan Ross D.123410ORCID

Affiliation:

1. Australian Cancer Research Foundation Department of Cancer Biology and Therapeutics, The John Curtin School of Medical Research, The Australian National University, Canberra, ACT, Australia;

2. Division of Cancer Research, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia;

3. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, VIC, Australia;

4. Department of Biochemistry and Molecular Biology, The University of Melbourne, Parkville, VIC, Australia;

5. Australian Centre for Blood Diseases, Monash University, Melbourne, VIC, Australia;

6. Division of Cancer Medicine, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia;

7. Victorian Cancer Cytogenetics Service, St. Vincent’s Hospital, Fitzroy, VIC, Australia;

8. Department of Medicine, St. Vincent’s Hospital, and

9. Department of Pathology, The University of Melbourne, Parkville, VIC, Australia;

10. School of Medical Sciences, University of Queensland, St. Lucia, QLD, Australia;

11. Division of Immunology, The Netherlands Cancer Institute, Amsterdam, The Netherlands;

12. Pimera Inc, San Diego, CA;

13. Clinical Haematology Unit, The Canberra Hospital, Canberra, ACT, Australia;

14. Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, SA, Australia;

15. Schools of Medicine and Biological Sciences, University of Adelaide, SA, Australia;

16. Research Institute of Molecular Pathology, Vienna, Austria;

17. Department of Clinical Haematology, The Alfred Hospital, Melbourne, VIC, Australia; and

18. Department of Biochemistry and Molecular Biology, Monash University, Melbourne, VIC, Australia

Abstract

Key Points Inhibition of RNA Pol I by CX-5461 treats aggressive AML and outperforms standard chemotherapy regimens. CX-5461 induces p53-dependent apoptosis, p53-independent cell-cycle defects and differentiation, and reduces LICs.

Publisher

American Society of Hematology

Subject

Cell Biology,Hematology,Immunology,Biochemistry

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