Therapeutic antagonists of microRNAs deplete leukemia-initiating cell activity
Chinavenmeni S. Velu, … , Brian Gebelein, H. Leighton Grimes
Chinavenmeni S. Velu, … , Brian Gebelein, H. Leighton Grimes
Published January 2, 2014; First published December 16, 2013
Citation Information: J Clin Invest. 2014;124(1):222-236. https://doi.org/10.1172/JCI66005.
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Research Article Oncology

Therapeutic antagonists of microRNAs deplete leukemia-initiating cell activity

Abstract

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.

Authors

Chinavenmeni S. Velu, Aditya Chaubey, James D. Phelan, Shane R. Horman, Mark Wunderlich, Monica L. Guzman, Anil G. Jegga, Nancy J. Zeleznik-Le, Jianjun Chen, James C. Mulloy, Jose A. Cancelas, Craig T. Jordan, Bruce J. Aronow, Guido Marcucci, Balkrishen Bhat, Brian Gebelein, H. Leighton Grimes

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Figure 2

Expression of miR-21 and miR-196b is regulated by endogenous and oncogenic levels of HOXA9.

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Expression of miR-21 and miR-196b is regulated by endogenous and oncogen...
(A) TaqMan analysis of the steady state level of mature miR-21, miR-196b, miR-155 (positive HOXA9 target gene control), and miR-224 (negative control) expression in Lin– BM cells with limiting alleles of Gfi1 and HoxA9 (n = 3). (B) Expression profiling of HOXA9, GFI1, MIR196B, and MIR21 in 7 de novo t(11q; 23) and 5 t(8; 21) AML samples. Expression data were mean centered (relative value scale shown in the bottom right). (C and D) TaqMan analysis of miR-21 (C) and miR-196b (D) expression in Lin– BM cells transduced with a retroviral vector encoding the indicated oncoprotein or empty vector (EV) (n = 3). *P < 0.05; **P < 0.01; ***P < 0.001.