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Molecular and Cellular Biology, August 2004, p. 6751-6762, Vol. 24, No. 15
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.15.6751-6762.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Thrombopoietin Induces HOXA9 Nuclear Transport in Immature Hematopoietic Cells: Potential Mechanism by Which the Hormone Favorably Affects Hematopoietic Stem Cells

Keita Kirito, Norma Fox, and Kenneth Kaushansky*

Division of Hematology/Oncology, Department of Medicine, University of California, San Diego, San Diego, California 92103-8811

Received 4 March 2004/ Accepted 10 May 2004

Members of the homeobox family of transcription factors are major regulators of hematopoiesis. Overexpression of either HOXB4 or HOXA9 in primitive marrow cells enhances the expansion of hematopoietic stem cells (HSCs). However, little is known of how expression or function of these proteins is regulated during hematopoiesis under physiological conditions. In our previous studies we demonstrated that thrombopoietin (TPO) enhances levels of HOXB4 mRNA in primitive hematopoietic cells (K. Kirito, N. Fox, and K. Kaushansky, Blood 102:3172-3178, 2003). To extend our studies, we investigated the effects of TPO on HOXA9 in this same cell population. Although overall levels of the transcription factor were not affected, we found that TPO induced the nuclear import of HOXA9 both in UT-7/TPO cells and in primitive Sca-1+/c-kit+/Gr-1– hematopoietic cells in a mitogen-activated protein kinase-dependent fashion. TPO also controlled MEIS1 expression at mRNA levels, at least in part due to phosphatidylinositol 3-kinase activation. Collectively, TPO modulates the function of HOXA9 by leading to its nuclear translocation, likely mediated by effects on its partner protein MEIS1, and potentially due to two newly identified nuclear localization signals. Our data suggest that TPO controls HSC development through the regulation of multiple members of the Hox family of transcription factors through multiple mechanisms.

* Corresponding author. Mailing address: Department of Medicine, University of California, San Diego, School of Medicine, 402 Dickinson St., Suite 380, San Diego, CA 92103-8811. Phone: (619) 543-6170. Fax: (619) 543-3931. E-mail: kkaushansky{at}ucsd.edu.

Molecular and Cellular Biology, August 2004, p. 6751-6762, Vol. 24, No. 15
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.15.6751-6762.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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