Deakin University
Browse

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

Download (2.81 MB)
journal contribution
posted on 2017-05-25, 00:00 authored by 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 GuthridgeMark Guthridge, Andrew Wei, Grant A McArthur, Richard B Pearson, Ross D Hannan
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.

History

Journal

Blood

Volume

129

Pagination

2882-2895

Location

New York, N.Y.

Open access

  • Yes

ISSN

0006-4971

eISSN

1528-0020

Language

eng

Publication classification

C1.1 Refereed article in a scholarly journal

Issue

21

Publisher

Grune & Stratton