Go to JCI Insight
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
  • Clinical Research and Public Health
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Gastroenterology
    • Immunology
    • Metabolism
    • Nephrology
    • Neuroscience
    • Oncology
    • Pulmonology
    • Vascular biology
    • All ...
  • Videos
    • Conversations with Giants in Medicine
    • Video Abstracts
  • Reviews
    • View all reviews ...
    • Complement Biology and Therapeutics (May 2025)
    • Evolving insights into MASLD and MASH pathogenesis and treatment (Apr 2025)
    • Microbiome in Health and Disease (Feb 2025)
    • Substance Use Disorders (Oct 2024)
    • Clonal Hematopoiesis (Oct 2024)
    • Sex Differences in Medicine (Sep 2024)
    • Vascular Malformations (Apr 2024)
    • View all review series ...
  • Viewpoint
  • Collections
    • In-Press Preview
    • Clinical Research and Public Health
    • Research Letters
    • Letters to the Editor
    • Editorials
    • Commentaries
    • Editor's notes
    • Reviews
    • Viewpoints
    • 100th anniversary
    • Top read articles

  • Current issue
  • Past issues
  • Specialties
  • Reviews
  • Review series
  • Conversations with Giants in Medicine
  • Video Abstracts
  • In-Press Preview
  • Clinical Research and Public Health
  • Research Letters
  • Letters to the Editor
  • Editorials
  • Commentaries
  • Editor's notes
  • Reviews
  • Viewpoints
  • 100th anniversary
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
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 December 16, 2013
Citation Information: J Clin Invest. 2014;124(1):222-236. https://doi.org/10.1172/JCI66005.
View: Text | PDF
Research Article Oncology Article has an altmetric score of 26

Therapeutic antagonists of microRNAs deplete leukemia-initiating cell activity

  • Text
  • PDF
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

×

Figure 6

Inhibition of miR-21 and miR-196b also interferes with maintenance of human MLL oncoprotein–initiated leukemia and extends life span in a human xenograft model.

Options: View larger image (or click on image) Download as PowerPoint
Inhibition of miR-21 and miR-196b also interferes with maintenance of hu...
(A) Enumeration of methylcellulose CFU assay with primary human AML with t(8;21) (AML-ETO) (patient 1) or 11q23 translocation cytogenetics (MLL) (2 independent human samples, patients 2 and 3) and NPM1 mutation (3 independent human samples, patients 4, 5, and 6) (n = 3, mean ± SD). (B) Scheme of experimental strategy showing transplant with MA9+NRAS leukemic cells into NSS mice, mouse numbers, and the treatment strategy and flow analysis. (C) Kaplan-Meier survival curve of nonirradiated NSS mice (mCD45+) transplanted with 0.5 × 106 hCD45+ MA9+NRAS leukemic cells. On day 25, the control group received PBS and the experimental group received chemotherapeutic agents for 5 days (3 days with Ara-C+Dox and the last 2 day only with Ara-C); mice were followed for survival. Transplanted mice were treated with antagomirs. Twenty-three days after transplantation, 6 week osmotic pumps containing A21+A196b or CA21+CA196b were implanted in the mice. On day 25, both groups received chemotherapeutic agents for 5 days (3 days with Ara-C+Dox and the last 2 day only with Ara-C) and they were followed for survival. Insets show flow plots of hCD45+ cells in moribund mice. *P < 0.05; **P < 0.01.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

Sign up for email alerts

Picked up by 3 news outlets
Posted by 3 X users
On 1 Facebook pages
103 readers on Mendeley
1 readers on CiteULike
See more details