Journal article

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 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 Show all

BLOOD | AMER SOC HEMATOLOGY | Published : 2017

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 o..

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Grants

Awarded by National Health and Medical Research Council (NHMRC) of Australia


Awarded by NHMRC program


Awarded by Cancer Council of Victoria


Funding Acknowledgements

This work was supported by project grants from the National Health and Medical Research Council (NHMRC) of Australia (#1043884, 251608, 566702, 166908, 251688, 509087, 400116, 400120, and 566876) and an NHMRC program grant (#1053792), and the Cancer Council of Victoria grant-in-aid (#1084545). The researchers were funded by the following: NHMRC fellowships (R.D.H., R.B.P., R.W.J., and G.A.M.), Cancer Council of Victoria, Cancer Council of Australian Capital Territory, Sir Edward Weary Dunlop fellowship (G.A.M.), and the Leukemia Foundation of Australia (grant-in-aid to M.W., and Ph.D. scholarships to D.P.C. and J.D.).