Aberrant Eukaryotic Translation Initiation Factor 4E-Dependent mRNA Transport Impedes Hematopoietic Differentiation and Contributes to Leukemogenesis

Abstract

The eukaryotic translation initiation factor 4E (eIF4E) acts as both a key translation factor and as a promoter of nucleocytoplasmic transport of specific transcripts. Traditionally, its transformation capacity in vivo is attributed to its role in translation initiation in the cytoplasm. Here, we demonstrate that elevated eIF4E impedes granulocytic and monocytic differentiation. Our subsequent mutagenesis studies indicate that this block is a result of dysregulated eIF4E-dependent mRNA transport. These studies indicate that the RNA transport function of eIF4E could contribute to leukemogenesis. We extended our studies to provide the first evidence that the nuclear transport function of eIF4E contributes to human malignancy, specifically in a subset of acute and chronic myelogenous leukemia patients. We observe an increase in eIF4E-dependent cyclin D1 mRNA transport and a concomitant increase in cyclin D1 protein levels. The aberrant nuclear function of eIF4E is due to abnormally large eIF4E bodies and the loss of regulation by the proline-rich homeodomain PRH. We developed a novel tool to modulate this transport activity. The introduction of IκB, the repressor of NF-κB, leads to suppression of eIF4E, elevation of PRH, reorganization of eIF4E nuclear bodies, and subsequent downregulation of eIF4E-dependent mRNA transport. Thus, our findings indicate that this nuclear function of eIF4E can contribute to leukemogenesis by promoting growth and by impeding differentiation.

ACKNOWLEDGMENTS

We are grateful for the kind gifts of antibodies and constructs from Paul Freemont, Gerd Maul, L. de Jong, Thomas Meier, Guy Sauvageau, Gary Nolan, David Grimwade, and Nahum Sonenberg. We thank Alex Kentsis for technical assistance and Liliana Ossowski for critical reading of the manuscript.

Confocal laser scanning microscopy was performed at the MSSM-LCSM core facility, supported with funding from NIH (1 S10 RR0 9145-01) and NSF (DBI-9724504). K.L.B.B. is a scholar of the Leukemia and Lymphoma Society. Financial support was provided by the NIH (CA 80728, CA88991, and CA90446) and by the Charlotte Geyer Cancer Foundation.