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https://hdl.handle.net/2440/106157
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Type: | Journal article |
Title: | Inhibition of Pol I transcription treats murine and human AML by targeting the leukemia-initiating cell population |
Author: | Hein, N. Cameron, D. Hannan, K. Nguyen, N. Fong, C. Sornkom, J. Wall, M. Pavy, M. Cullinane, C. Diesch, J. Devlin, J. George, A. Sanij, E. Quin, J. Poortinga, G. Verbrugge, I. Baker, A. Drygin, D. Harrison, S. Rozario, J. et al. |
Citation: | Blood, 2017; 129(21):2882-2895 |
Publisher: | American Society of Hematology |
Issue Date: | 2017 |
ISSN: | 0006-4971 1528-0020 |
Statement of Responsibility: | Nadine Hein, Donald P. Cameron, Katherine M. Hannan, Nhu-Y N. Nguyen, Chun Yew Fong, Jirawas Sornkom, Meaghan Wall, Megan Pavy, Carleen Cullinane, Jeannine Diesch, Jennifer R. Devlin, Amee J. George, Elaine Sanij, Jaclyn Quin, Gretchen Poortinga, Inge Verbrugge, Adele Baker, Denis Drygin, Simon J. Harrison, James D. Rozario, Jason A. Powell, Stuart M. Pitson, Johannes Zuber, Ricky W. Johnstone, Mark A. Dawson, Mark A. Guthridge, Andrew Wei, Grant A. McArthur, Richard B. Pearson and Ross D. Hannan |
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. |
Keywords: | Cell Line, Tumor Animals Mice, Inbred NOD Humans Mice Mice, Mutant Strains Naphthyridines Pol1 Transcription Initiation Complex Proteins Cell Division G2 Phase Transcription, Genetic Tumor Suppressor Protein p53 Benzothiazoles Neoplastic Stem Cells Leukemia, Myeloid, Acute Checkpoint Kinase 2 Checkpoint Kinase 1 |
Rights: | © 2017 by The American Society of Hematology |
DOI: | 10.1182/blood-2016-05-718171 |
Grant ID: | http://purl.org/au-research/grants/nhmrc/1043884 http://purl.org/au-research/grants/nhmrc/251608 http://purl.org/au-research/grants/nhmrc/566702 http://purl.org/au-research/grants/nhmrc/166908 http://purl.org/au-research/grants/nhmrc/251688 http://purl.org/au-research/grants/nhmrc/509087 http://purl.org/au-research/grants/nhmrc/400116 http://purl.org/au-research/grants/nhmrc/400120 http://purl.org/au-research/grants/nhmrc/566876 http://purl.org/au-research/grants/nhmrc/1053792 NHMRC |
Published version: | http://dx.doi.org/10.1182/blood-2016-05-718171 |
Appears in Collections: | Aurora harvest 8 Medicine publications |
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