Inhibition of Pol I transcription treats murine and human AML by targeting the leukemia-initiating cell population.
Blood
; 129(21): 2882-2895, 2017 05 25.
Article
en En
| MEDLINE
| ID: mdl-28283481
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.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Transcripción Genética
/
Células Madre Neoplásicas
/
Leucemia Mieloide Aguda
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Proteínas del Complejo de Iniciación de Transcripción Pol1
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Benzotiazoles
/
Naftiridinas
Límite:
Animals
/
Humans
Idioma:
En
Revista:
Blood
Año:
2017
Tipo del documento:
Article
País de afiliación:
Australia