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Inhibition of Pol I transcription treats murine and human AML by targeting the leukemia-initiating cell population.
Hein, Nadine; Cameron, Donald P; Hannan, Katherine M; Nguyen, Nhu-Y N; Fong, Chun Yew; Sornkom, Jirawas; Wall, Meaghan; Pavy, Megan; Cullinane, Carleen; Diesch, Jeannine; Devlin, Jennifer R; George, Amee J; Sanij, Elaine; Quin, Jaclyn; Poortinga, Gretchen; Verbrugge, Inge; Baker, Adele; Drygin, Denis; Harrison, Simon J; Rozario, James D; Powell, Jason A; Pitson, Stuart M; Zuber, Johannes; Johnstone, Ricky W; Dawson, Mark A; Guthridge, Mark A; Wei, Andrew; McArthur, Grant A; Pearson, Richard B; Hannan, Ross D.
Afiliação
  • Hein N; Australian Cancer Research Foundation Department of Cancer Biology and Therapeutics, The John Curtin School of Medical Research, The Australian National University, Canberra, ACT, Australia.
  • Cameron DP; Division of Cancer Research, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia.
  • Hannan KM; Australian Cancer Research Foundation Department of Cancer Biology and Therapeutics, The John Curtin School of Medical Research, The Australian National University, Canberra, ACT, Australia.
  • Nguyen NN; Division of Cancer Research, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia.
  • Fong CY; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, VIC, Australia.
  • Sornkom J; Australian Cancer Research Foundation Department of Cancer Biology and Therapeutics, The John Curtin School of Medical Research, The Australian National University, Canberra, ACT, Australia.
  • Wall M; Division of Cancer Research, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia.
  • Pavy M; Department of Biochemistry and Molecular Biology, The University of Melbourne, Parkville, VIC, Australia.
  • Cullinane C; Australian Centre for Blood Diseases, Monash University, Melbourne, VIC, Australia.
  • Diesch J; Division of Cancer Research, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia.
  • Devlin JR; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, VIC, Australia.
  • George AJ; Division of Cancer Medicine, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia.
  • Sanij E; Division of Cancer Research, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia.
  • Quin J; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, VIC, Australia.
  • Poortinga G; Victorian Cancer Cytogenetics Service, St. Vincent's Hospital, Fitzroy, VIC, Australia.
  • Verbrugge I; Department of Medicine, St. Vincent's Hospital, and.
  • Baker A; Australian Cancer Research Foundation Department of Cancer Biology and Therapeutics, The John Curtin School of Medical Research, The Australian National University, Canberra, ACT, Australia.
  • Drygin D; Division of Cancer Research, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia.
  • Harrison SJ; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, VIC, Australia.
  • Rozario JD; Division of Cancer Research, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia.
  • Powell JA; Division of Cancer Research, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia.
  • Pitson SM; Australian Cancer Research Foundation Department of Cancer Biology and Therapeutics, The John Curtin School of Medical Research, The Australian National University, Canberra, ACT, Australia.
  • Zuber J; Department of Pathology, The University of Melbourne, Parkville, VIC, Australia.
  • Johnstone RW; School of Medical Sciences, University of Queensland, St. Lucia, QLD, Australia.
  • Dawson MA; Division of Cancer Research, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia.
  • Guthridge MA; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, VIC, Australia.
  • Wei A; Department of Pathology, The University of Melbourne, Parkville, VIC, Australia.
  • McArthur GA; Division of Cancer Research, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia.
  • Pearson RB; Division of Cancer Research, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia.
  • Hannan RD; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, VIC, Australia.
Blood ; 129(21): 2882-2895, 2017 05 25.
Article em En | MEDLINE | ID: mdl-28283481
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.
Assuntos

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Transcrição Gênica / Células-Tronco Neoplásicas / Leucemia Mieloide Aguda / Proteínas Pol1 do Complexo de Iniciação de Transcrição / Benzotiazóis / Naftiridinas Limite: Animals / Humans Idioma: En Ano de publicação: 2017 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Transcrição Gênica / Células-Tronco Neoplásicas / Leucemia Mieloide Aguda / Proteínas Pol1 do Complexo de Iniciação de Transcrição / Benzotiazóis / Naftiridinas Limite: Animals / Humans Idioma: En Ano de publicação: 2017 Tipo de documento: Article