title: Inhibition of Pol I transcription treats murine and human AML by targeting the leukemia-initiating cell population.
abstract: Despite the development of novel drugs, the prospects for many patients with acute myeloid leukemia (AML) remain dismal. This study reveals that the selective inhibitor of RNA polymerase I (Pol I) transcription, CX-5461, effectively treats aggressive AML, including mixed-lineage leukemia-driven AML, and outperforms standard chemotherapies. In addition to the previously characterized mechanism of action of CX-5461 (ie, the induction of p53-dependent apoptotic cell death), the inhibition of Pol I transcription also demonstrates potent efficacy in p53null AML in vivo. This significant survival advantage in both p53WT and p53null leukemic mice treated with CX-5461 is associated with activation of the checkpoint kinases 1/2, an aberrant G2/M cell-cycle progression and induction of myeloid differentiation of the leukemic blasts. The ability to target the leukemic-initiating cell population is thought to be essential for lasting therapeutic benefit. Most strikingly, the acute inhibition of Pol I transcription reduces both the leukemic granulocyte-macrophage progenitor and leukemia-initiating cell (LIC) populations, and suppresses their clonogenic capacity. This suggests that dysregulated Pol I transcription is essential for the maintenance of their leukemia-initiating potential. Together, these findings demonstrate the therapeutic utility of this new class of inhibitors to treat highly aggressive AML by targeting LICs.
authors.affiliation: Australian Cancer Research Foundation Department of Cancer Biology and Therapeutics, The John Curtin School of Medical Research, The Australian National University, Canberra, ACT, Australia.|Division of Cancer Research, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia.
authors.forename: Nadine
authors.initials: N
authors.lastname: Hein
authors.affiliation: Australian Cancer Research Foundation Department of Cancer Biology and Therapeutics, The John Curtin School of Medical Research, The Australian National University, Canberra, ACT, Australia.|Division of Cancer Research, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia.|Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, VIC, Australia.
authors.forename: Donald P
authors.identifier: 0000-0002-3175-6965
authors.initials: DP
authors.lastname: Cameron
authors.affiliation: Australian Cancer Research Foundation Department of Cancer Biology and Therapeutics, The John Curtin School of Medical Research, The Australian National University, Canberra, ACT, Australia.|Division of Cancer Research, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia.|Department of Biochemistry and Molecular Biology, The University of Melbourne, Parkville, VIC, Australia.
authors.forename: Katherine M
authors.identifier: 0000-0003-4186-8167
authors.initials: KM
authors.lastname: Hannan
authors.affiliation: Australian Centre for Blood Diseases, Monash University, Melbourne, VIC, Australia.
authors.forename: Nhu-Y N
authors.initials: NN
authors.lastname: Nguyen
authors.affiliation: Division of Cancer Research, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia.|Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, VIC, Australia.|Division of Cancer Medicine, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia.
authors.forename: Chun Yew
authors.initials: CY
authors.lastname: Fong
authors.affiliation: Division of Cancer Research, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia.|Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, VIC, Australia.
authors.forename: Jirawas
authors.initials: J
authors.lastname: Sornkom
authors.affiliation: Victorian Cancer Cytogenetics Service, St. Vincent's Hospital, Fitzroy, VIC, Australia.|Department of Medicine, St. Vincent's Hospital, and.
authors.forename: Meaghan
authors.initials: M
authors.lastname: Wall
authors.affiliation: Australian Cancer Research Foundation Department of Cancer Biology and Therapeutics, The John Curtin School of Medical Research, The Australian National University, Canberra, ACT, Australia.
authors.forename: Megan
authors.initials: M
authors.lastname: Pavy
authors.affiliation: Division of Cancer Research, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia.|Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, VIC, Australia.
authors.forename: Carleen
authors.initials: C
authors.lastname: Cullinane
authors.affiliation: Division of Cancer Research, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia.
authors.forename: Jeannine
authors.initials: J
authors.lastname: Diesch
authors.affiliation: Division of Cancer Research, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia.
authors.forename: Jennifer R
authors.initials: JR
authors.lastname: Devlin
authors.affiliation: Australian Cancer Research Foundation Department of Cancer Biology and Therapeutics, The John Curtin School of Medical Research, The Australian National University, Canberra, ACT, Australia.|Department of Pathology, The University of Melbourne, Parkville, VIC, Australia.|School of Medical Sciences, University of Queensland, St. Lucia, QLD, Australia.
authors.forename: Amee J
authors.identifier: 0000-0002-0265-4476
authors.initials: AJ
authors.lastname: George
authors.affiliation: Division of Cancer Research, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia.|Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, VIC, Australia.|Department of Pathology, The University of Melbourne, Parkville, VIC, Australia.
authors.forename: Elaine
authors.initials: E
authors.lastname: Sanij
authors.affiliation: Division of Cancer Research, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia.
authors.forename: Jaclyn
authors.initials: J
authors.lastname: Quin
authors.affiliation: Division of Cancer Research, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia.|Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, VIC, Australia.|Department of Pathology, The University of Melbourne, Parkville, VIC, Australia.
authors.forename: Gretchen
authors.initials: G
authors.lastname: Poortinga
authors.affiliation: Division of Immunology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors.forename: Inge
authors.initials: I
authors.lastname: Verbrugge
authors.affiliation: Division of Cancer Research, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia.
authors.forename: Adele
authors.initials: A
authors.lastname: Baker
authors.affiliation: Pimera Inc, San Diego, CA.
authors.forename: Denis
authors.initials: D
authors.lastname: Drygin
authors.affiliation: Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, VIC, Australia.|Division of Cancer Medicine, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia.
authors.forename: Simon J
authors.identifier: 0000-0003-4555-6582
authors.initials: SJ
authors.lastname: Harrison
authors.affiliation: Clinical Haematology Unit, The Canberra Hospital, Canberra, ACT, Australia.
authors.forename: James D
authors.identifier: 0000-0002-5983-753X
authors.initials: JD
authors.lastname: Rozario
authors.affiliation: Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, SA, Australia.|Schools of Medicine and Biological Sciences, University of Adelaide, SA, Australia.
authors.forename: Jason A
authors.initials: JA
authors.lastname: Powell
authors.affiliation: Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, SA, Australia.|Schools of Medicine and Biological Sciences, University of Adelaide, SA, Australia.
authors.forename: Stuart M
authors.identifier: 0000-0002-9527-2740
authors.initials: SM
authors.lastname: Pitson
authors.affiliation: Research Institute of Molecular Pathology, Vienna, Austria.
authors.forename: Johannes
authors.identifier: 0000-0001-8810-6835
authors.initials: J
authors.lastname: Zuber
authors.affiliation: Division of Cancer Research, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia.|Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, VIC, Australia.|Department of Pathology, The University of Melbourne, Parkville, VIC, Australia.
authors.forename: Ricky W
authors.initials: RW
authors.lastname: Johnstone
authors.affiliation: Division of Cancer Research, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia.|Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, VIC, Australia.|Division of Cancer Medicine, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia.
authors.forename: Mark A
authors.identifier: 0000-0002-5464-5029
authors.initials: MA
authors.lastname: Dawson
authors.affiliation: Australian Centre for Blood Diseases, Monash University, Melbourne, VIC, Australia.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Guthridge
authors.affiliation: Australian Centre for Blood Diseases, Monash University, Melbourne, VIC, Australia.|Department of Clinical Haematology, The Alfred Hospital, Melbourne, VIC, Australia; and.
authors.forename: Andrew
authors.initials: A
authors.lastname: Wei
authors.affiliation: Division of Cancer Research, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia.|Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, VIC, Australia.|Division of Cancer Medicine, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia.
authors.forename: Grant A
authors.initials: GA
authors.lastname: McArthur
authors.affiliation: Division of Cancer Research, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia.|Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, VIC, Australia.|Department of Biochemistry and Molecular Biology, The University of Melbourne, Parkville, VIC, Australia.|Department of Biochemistry and Molecular Biology, Monash University, Melbourne, VIC, Australia.
authors.forename: Richard B
authors.initials: RB
authors.lastname: Pearson
authors.affiliation: Australian Cancer Research Foundation Department of Cancer Biology and Therapeutics, The John Curtin School of Medical Research, The Australian National University, Canberra, ACT, Australia.|Division of Cancer Research, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia.|Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, VIC, Australia.|Department of Biochemistry and Molecular Biology, The University of Melbourne, Parkville, VIC, Australia.|School of Medical Sciences, University of Queensland, St. Lucia, QLD, Australia.|Department of Biochemistry and Molecular Biology, Monash University, Melbourne, VIC, Australia.
authors.forename: Ross D
authors.identifier: 0000-0002-2166-4493
authors.initials: RD
authors.lastname: Hannan
mesh_terms: D000818:Animals; D052160:Benzothiazoles / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D000071877:Checkpoint Kinase 1 / Q000235:genetics / Q000378:metabolism; D064447:Checkpoint Kinase 2 / Q000235:genetics / Q000378:metabolism; D016195:G2 Phase / Q000187:drug effects / Q000235:genetics; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000453:epidemiology / Q000235:genetics / Q000473:pathology; D051379:Mice; D016688:Mice, Inbred NOD; D008817:Mice, Mutant Strains; D009287:Naphthyridines / Q000494:pharmacology*; D014411:Neoplastic Stem Cells / Q000201:enzymology* / Q000473:pathology; D035463:Pol1 Transcription Initiation Complex Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
chemical_list: D052160:Benzothiazoles; C557717:CX 5461; D009287:Naphthyridines; D035463:Pol1 Transcription Initiation Complex Proteins; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D064447:Checkpoint Kinase 2; C000605867:CHEK1 protein, human; C578634:CHEK2 protein, human; D000071877:Checkpoint Kinase 1; C000605869:Chek1 protein, mouse; C578633:Chek2 protein, mouse