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Molecular and Cellular Biology, December 2003, p. 8992-9002, Vol. 23, No. 24
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.24.8992-9002.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

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

Ivan Topisirovic,1 Monica L. Guzman,2,{dagger} Melanie J. McConnell,3 Jonathan D. Licht,3 Biljana Culjkovic,1 Sarah J. Neering,2,{dagger} Craig T. Jordan,2,{dagger} and Katherine L. B. Borden1*

Structural Biology Program, Department of Physiology and Biophysics,1 Department of Medicine, Mount Sinai School of Medicine, New York University, New York, New York 10029,3 Blood and Marrow Transplant Program, Markey Cancer Center, Division of Hematology Oncology, University of Kentucky Medical Center, Lexington, Kentucky 405362

Received 28 May 2003/ Returned for modification 7 August 2003/ Accepted 15 September 2003

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 I{kappa}B, the repressor of NF-{kappa}B, 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.

* Corresponding author. Mailing address: Department of Physiology and Biophysics, Mount Sinai School of Medicine, New York University, One Gustave Levy Place, New York, NY 10029. Phone: (212) 659-8677. Fax: (212) 849-2456. E-mail: kathy{at}physbio.mssm.edu.

{dagger} Present address: University of Rochester School of Medicine, Rochester, NY 14642.

Molecular and Cellular Biology, December 2003, p. 8992-9002, Vol. 23, No. 24
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.24.8992-9002.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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