Title |
Inhibition of Pol I transcription treats murine and human AML by targeting the leukemia-initiating cell population
|
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Published in |
Blood, March 2017
|
DOI | 10.1182/blood-2016-05-718171 |
Pubmed ID | |
Authors |
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, Ross D Hannan |
Abstract |
Despite the development of novel drugs, 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 MLL-driven AML, and outperforms standard chemotherapies. In addition to the previously characterized mechanism of action of CX-5461, the induction of p53-dependant apoptotic cell death, 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 CHK1/CHK2, 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, 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 leukemia initiating cells. |
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Geographical breakdown
Country | Count | As % |
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United States | 2 | 15% |
United Kingdom | 2 | 15% |
Australia | 2 | 15% |
Saudi Arabia | 1 | 8% |
Turkey | 1 | 8% |
Unknown | 5 | 38% |
Demographic breakdown
Type | Count | As % |
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Members of the public | 5 | 38% |
Scientists | 4 | 31% |
Science communicators (journalists, bloggers, editors) | 4 | 31% |
Mendeley readers
Geographical breakdown
Country | Count | As % |
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Unknown | 78 | 100% |
Demographic breakdown
Readers by professional status | Count | As % |
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Researcher | 14 | 18% |
Student > Master | 11 | 14% |
Student > Bachelor | 11 | 14% |
Student > Ph. D. Student | 7 | 9% |
Professor | 5 | 6% |
Other | 14 | 18% |
Unknown | 16 | 21% |
Readers by discipline | Count | As % |
---|---|---|
Biochemistry, Genetics and Molecular Biology | 24 | 31% |
Medicine and Dentistry | 14 | 18% |
Agricultural and Biological Sciences | 11 | 14% |
Pharmacology, Toxicology and Pharmaceutical Science | 2 | 3% |
Chemistry | 2 | 3% |
Other | 6 | 8% |
Unknown | 19 | 24% |