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

• Published in: Cell 2010-03, Vol.140 (5), p.652-665
• Main Authors: Eiring, Anna M., Harb, Jason G., Neviani, Paolo, Garton, Christopher, Oaks, Joshua J., Spizzo, Riccardo, Liu, Shujun, Schwind, Sebastian, Santhanam, Ramasamy, Hickey, Christopher J., Becker, Heiko, Chandler, Jason C., Andino, Raul, Cortes, Jorge, Hokland, Peter, Huettner, Claudia S., Bhatia, Ravi, Roy, Denis C., Liebhaber, Stephen A., Caligiuri, Michael A., Marcucci, Guido, Garzon, Ramiro, Croce, Carlo M., Calin, George A., Perrotti, Danilo
• Format: Article
• Language: English
• Subjects: Animals; Blast Crisis; CCAAT-Enhancer-Binding Proteins - metabolism; Cell Line, Tumor; Heterogeneous-Nuclear Ribonucleoproteins - genetics; Heterogeneous-Nuclear Ribonucleoproteins - metabolism; Humans; HUMDISEASE; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - genetics; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - metabolism; Mice; MicroRNAs - metabolism; Proto-Oncogene Proteins c-pim-1 - metabolism; RNA; RNA-Induced Silencing Complex - metabolism
• ISSN: 0092-8674; 1097-4172
• DOI: 10.1016/j.cell.2010.01.007

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. [Display omitted] [Display omitted] ► Expression of miR-328 is reduced in CD34 + CML blast crisis (CML-BC) progenitors ► miR-328 directly binds hnRNP E2 and rescues CEBPA mRNA translation ► miR-328 restores C/EBPα-dependent maturation of myeloid CML-BC progenitors ► miR-328 pairs with PIM1 3′UTR and impairs survival of CML-BC progenitors