martes, 17 de diciembre de 2013

JCI - Therapeutic antagonists of microRNAs deplete leukemia-initiating cell activity

OPEN ►
JCI - Therapeutic antagonists of microRNAs deplete leukemia-initiating cell activity

Research Article

Therapeutic antagonists of microRNAs deplete leukemia-initiating cell activity

Chinavenmeni S. Velu1Aditya Chaubey1James D. Phelan1,Shane R. Horman1Mark Wunderlich2Monica L. Guzman3,Anil G. Jegga4Nancy J. Zeleznik-Le5Jianjun Chen6,James C. Mulloy2Jose A. Cancelas2Craig T. Jordan7,Bruce J. Aronow4Guido Marcucci8Balkrishen Bhat9,Brian Gebelein10 and H. Leighton Grimes1,2
1Division of Immunobiology and
2Division of Experimental Hematology and Cancer Biology, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio, USA.
3Weill Cornell College of Medicine, New York, New York, USA.
4Division of Biomedical Informatics, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio, USA.
5Loyola University Medical Center, Maywood, Illinois, USA.
6University of Chicago, Chicago, Illinois, USA.
7University of Colorado, Aurora, Colorado, USA.
8The Ohio State University Comprehensive Cancer Center, Columbus, Ohio, USA.
9Regulus Therapeutics, San Diego, California, USA.
10Division of Developmental Biology, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio, USA.
Address correspondence to: H. Leighton Grimes, Division of Immunology, 3333 Burnet Ave., MLC 7038, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio 45229, USA. Phone: 513.636.6089; Fax: 513.636.5355; E-mail: Lee.Grimes@cchmc.org.
Authorship note: Chinavenmeni S. Velu and Aditya Chaubey contributed equally to this work.
Published December 16, 2013
Received for publication July 25, 2012, and accepted in revised form October 10, 2013.
Acute myelogenous leukemia (AML) subtypes that result from oncogenic activation of homeobox (HOX) transcription factors are associated with poor prognosis. The HOXA9 transcription activator and growth factor independent 1 (GFI1) transcriptional repressor compete for occupancy at DNA-binding sites for the regulation of common target genes. We exploited this HOXA9 versus GFI1 antagonism to identify the genes encoding microRNA-21 and microRNA-196b as transcriptional targets of HOX-based leukemia oncoproteins. Therapeutic inhibition of microRNA-21 and microRNA-196b inhibited in vitro leukemic colony forming activity and depleted in vivo leukemia-initiating cell activity of HOX-based leukemias, which led to leukemia-free survival in a murine AML model and delayed disease onset in xenograft models. These data establish microRNA as functional effectors of endogenous HOXA9 and HOX-based leukemia oncoproteins, provide a concise in vivo platform to test RNA therapeutics, and suggest therapeutic value for microRNA antagonists in AML.

No hay comentarios:

Publicar un comentario