1. Inhibition of Pol I transcription treats murine and human AML by targeting the leukemia-initiating cell population
- Author
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Grant A. McArthur, James D. Rozario, Meaghan Wall, Denis Drygin, Gretchen Poortinga, Adele Baker, Ross D. Hannan, Donald P. Cameron, Katherine M. Hannan, Carleen Cullinane, Johannes Zuber, Mark A. Guthridge, Jennifer R. Devlin, Elaine Sanij, Jirawas Sornkom, Mark A. Dawson, Nadine Hein, Nhu Y.N. Nguyen, Amee J George, Chun Yew Fong, Simon J. Harrison, Ricky W. Johnstone, Jaclyn E Quin, Megan Pavy, Jeannine Diesch, Richard B. Pearson, Inge Verbrugge, Stuart M. Pitson, Jason A. Powell, Andrew H. Wei, Hein, Nadine, Cameron, Donald P, Hannan, Katherine M, Nguyen, Nhu-YN, Powell, Jason A, Pitson, Stuart M, and Hannan, Ross D
- Subjects
0301 basic medicine ,G2 Phase ,Myeloid ,Transcription, Genetic ,Immunology ,Cell ,Population ,Biology ,Biochemistry ,03 medical and health sciences ,Mice ,0302 clinical medicine ,AML ,Transcription (biology) ,Mice, Inbred NOD ,hemic and lymphatic diseases ,Cell Line, Tumor ,medicine ,Animals ,Humans ,CHEK1 ,Benzothiazoles ,Naphthyridines ,education ,education.field_of_study ,Myeloid Neoplasia ,chemotharapies ,leukemia ,Myeloid leukemia ,Cell Biology ,Hematology ,medicine.disease ,Mice, Mutant Strains ,Leukemia ,Checkpoint Kinase 2 ,Leukemia, Myeloid, Acute ,030104 developmental biology ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Checkpoint Kinase 1 ,Cancer research ,Neoplastic Stem Cells ,Stem cell ,Tumor Suppressor Protein p53 ,Pol1 Transcription Initiation Complex Proteins ,Cell Division - 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. Refereed/Peer-reviewed
- Published
- 2016