miR-328 functions as an RNA decoy to modulate hnRNP E2 regulation of mRNA translation in leukemic blasts.
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.
Eiring
Anna M
AM
Human Cancer Genetics Program, Department of Molecular Virology, Immunology, and Medical Genetics, The Ohio State University, Columbus, OH 43210, USA.
Harb
Jason G
JG
Neviani
Paolo
P
Garton
Christopher
C
Oaks
Joshua J
JJ
Spizzo
Riccardo
R
Liu
Shujun
S
Schwind
Sebastian
S
Santhanam
Ramasamy
R
Hickey
Christopher J
CJ
Becker
Heiko
H
Chandler
Jason C
JC
Andino
Raul
R
Cortes
Jorge
J
Hokland
Peter
P
Huettner
Claudia S
CS
Bhatia
Ravi
R
Roy
Denis C
DC
Liebhaber
Stephen A
SA
Caligiuri
Michael A
MA
Marcucci
Guido
G
Garzon
Ramiro
R
Croce
Carlo M
CM
Calin
George A
GA
Perrotti
Danilo
D
D000818:Animals; D001752:Blast Crisis; D022762:CCAAT-Enhancer-Binding Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D034441:Heterogeneous-Nuclear Ribonucleoproteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D035683:MicroRNAs / Q000378:metabolism*; D051573:Proto-Oncogene Proteins c-pim-1 / Q000378:metabolism; D034743:RNA-Induced Silencing Complex / Q000378:metabolism
D022762:CCAAT-Enhancer-Binding Proteins; C515848:CEBPA protein, human; D034441:Heterogeneous-Nuclear Ribonucleoproteins; C548170:MIRN328 microRNA, human; C548169:MIRN328 microRNA, mouse; D035683:MicroRNAs; D034743:RNA-Induced Silencing Complex; C496634:PIM1 protein, human; D051573:Proto-Oncogene Proteins c-pim-1