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

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 this new class of inhibitors to treat highly aggressive AML by targeting LICs.

• 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
• Journal: Blood (Blood) Vol. 129 Issue 21 Pg. 2882-2895 (05 25 2017) ISSN: 1528-0020 [Electronic] United States
• PMID: 28283481 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2017 by The American Society of Hematology.

Chemical References

• Benzothiazoles
• CX 5461
• Naphthyridines
• Pol1 Transcription Initiation Complex Proteins
• TP53 protein, human
• Tumor Suppressor Protein p53
• Checkpoint Kinase 2
• CHEK1 protein, human
• CHEK2 protein, human
• Checkpoint Kinase 1
• Chek1 protein, mouse
• Chek2 protein, mouse

Topics

• Animals
• Benzothiazoles (pharmacology)
• Cell Division (drug effects, genetics)
• Cell Line, Tumor
• Checkpoint Kinase 1 (genetics, metabolism)
• Checkpoint Kinase 2 (genetics, metabolism)
• G2 Phase (drug effects, genetics)
• Humans
• Leukemia, Myeloid, Acute (drug therapy, epidemiology, genetics, pathology)
• Mice
• Mice, Inbred NOD
• Mice, Mutant Strains
• Naphthyridines (pharmacology)
• Neoplastic Stem Cells (enzymology, pathology)
• Pol1 Transcription Initiation Complex Proteins (antagonists & inhibitors, genetics, metabolism)
• Transcription, Genetic (drug effects)
• Tumor Suppressor Protein p53 (genetics, metabolism)