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

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,...

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Bibliographic Details
Published in:Blood 2017-05, Vol.129 (21), p.2882-2895
Main Authors: Hein, Nadine, Cameron, Donald P., Hannan, Katherine M., Nguyen, Nhu-Y N., Fong, Chun Yew, Sornkom, Jirawas, Wall, Meaghan, Pavy, Megan, Cullinane, Carleen, Diesch, Jeannine, Devlin, Jennifer R., George, Amee J., Sanij, Elaine, Quin, Jaclyn, Poortinga, Gretchen, Verbrugge, Inge, Baker, Adele, Drygin, Denis, Harrison, Simon J., Rozario, James D., Powell, Jason A., Pitson, Stuart M., Zuber, Johannes, Johnstone, Ricky W., Dawson, Mark A., Guthridge, Mark A., Wei, Andrew, McArthur, Grant A., Pearson, Richard B., Hannan, Ross D.
Format: Article
Language:English
Subjects:
Animals
Benzothiazoles - pharmacology
Cell Division - drug effects
Cell Division - genetics
Cell Line, Tumor
Checkpoint Kinase 1 - genetics
Checkpoint Kinase 1 - metabolism
Checkpoint Kinase 2 - genetics
Checkpoint Kinase 2 - metabolism
G2 Phase - drug effects
G2 Phase - genetics
Humans
Leukemia, Myeloid, Acute - drug therapy
Leukemia, Myeloid, Acute - epidemiology
Leukemia, Myeloid, Acute - genetics
Leukemia, Myeloid, Acute - pathology
Mice
Mice, Inbred NOD
Mice, Mutant Strains
Myeloid Neoplasia
Naphthyridines - pharmacology
Neoplastic Stem Cells - enzymology
Neoplastic Stem Cells - pathology
Pol1 Transcription Initiation Complex Proteins - antagonists & inhibitors
Pol1 Transcription Initiation Complex Proteins - genetics
Pol1 Transcription Initiation Complex Proteins - metabolism
Transcription, Genetic - drug effects
Tumor Suppressor Protein p53 - genetics
Tumor Suppressor Protein p53 - metabolism
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Summary: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. •Inhibition of RNA Pol I by CX-5461 treats aggressive AML and outperforms standard chemotherapy regimens.•CX-5461 induces p53-dependent apoptosis, p53-independent cell-cycle defects and differentiation, and reduces LICs.
ISSN:0006-4971
1528-0020
DOI:10.1182/blood-2016-05-718171