miR-328 Functions as an RNA Decoy to Modulate hnRNP E2 Regulation of mRNA Translation in Leukemic Blasts

Anna M. Eiring, Jason G. Harb, Paolo Neviani, Christopher Garton, Joshua J. Oaks, Riccardo Spizzo, Shujun Liu, Sebastian Schwind, Ramasamy Santhanam, Christopher J. Hickey, Heiko Becker, Jason C. Chandler, Raul Andino, Jorge Cortes, Peter Hokland, Claudia S. Huettner, Ravi Bhatia, Denis C. Roy, Stephen A. Liebhaber, Michael A. CaligiuriGuido Marcucci, Ramiro Garzon, Carlo M. Croce, George A. Calin, Danilo Perrotti

Research output: Contribution to journalArticlepeer-review

390 Scopus citations

Abstract

MicroRNAs and heterogeneous ribonucleoproteins (hnRNPs) are posttranscriptional gene regulators that bind mRNA in a sequence-specific manner. Here, we report that loss of miR-328 occurs in blast crisis chronic myelogenous leukemia (CML-BC) in a BCR/ABL dose- and kinase-dependent manner through the MAPK-hnRNP E2 pathway. Restoration of miR-328 expression rescues differentiation and impairs survival of leukemic blasts by simultaneously interacting with the translational regulator poly(rC)-binding protein hnRNP E2 and with the mRNA encoding the survival factor PIM1, respectively. The interaction with hnRNP E2 is independent of the microRNA's seed sequence and it leads to release of CEBPA mRNA from hnRNP E2-mediated translational inhibition. Altogether, these data reveal the dual ability of a microRNA to control cell fate both through base pairing with mRNA targets and through a decoy activity that interferes with the function of regulatory proteins. PaperFlick: {An electronic component is presented}.

Original languageEnglish (US)
Pages (from-to)652-665
Number of pages14
JournalCell
Volume140
Issue number5
DOIs
StatePublished - Mar 5 2010
Externally publishedYes

Bibliographical note

Funding Information:
This work was supported in part by grants from the National Cancer Institute CA095512 (D.P.), CA16058 (OSU-CCC), NIH, Bethesda, MD, USA; the US Army, CML Research Program, W81XWH-07-1-0270 (D.P.); the American-Italian Cancer Foundation (P.N.); Fonds de la Recherche en Sante du Quebec (D.C.R.); and AGGRS from The OSU Graduate School (A.M.E.). D.P. is a Scholar of The Leukemia and Lymphoma Society. G.A.C. is a Fellow of the M.D. Anderson Research Trust and Scholar of the University of Texas System Regents. We thank J.-S. Chang, M. Odeh, and A. Martin for technical assistance and S. Lee for editorial assistance; T. Skorski (Temple University, Philadelphia, PA, USA) for providing PIM1 cDNAs; F. Racke (OSU, Columbus OH, USA) for histopathology analysis; B. Calabretta (TJU, Philadelphia, PA, USA), R. Arlinghaus (MDACC, Houston, TX, USA), and K. Huebner (OSU) for critical reading of the manuscript.

Keywords

  • HUMDISEASE
  • RNA

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