Inhibition of Pol I transcription treats murine and human AML by targeting the leukemia-initiating cell population

Nadine Hein, Donald P. Cameron, Katherine M Hannan, Nhu Y.N. Nguyen, Chun Yew Fong, Jirawas Sornkom, Meaghan Wall, Megan Pavy, Carleen M Cullinane, Jeannine Diesch, Jennifer R Devlin, Amee J. George, Elaine Sanij, Jaclyn E Quin, Gretchen Poortinga, Inge Verbrugge, Adele Baker, Denis J Drygin, Simon James Harrison, James D. RozarioJason 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

Research output: Contribution to journalArticleResearchpeer-review

30 Citations (Scopus)

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 thisnewclass of inhibitors to treat highly aggressive AML by targeting LICs.

Original languageEnglish
Pages (from-to)2882-2895
Number of pages14
JournalBlood
Volume129
Issue number21
DOIs
Publication statusPublished - 25 May 2017

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