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Molecular and Cellular Biology, September 2009, p. 5181-5192, Vol. 29, No. 18
0270-7306/09/$08.00+0     doi:10.1128/MCB.00545-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

HOXA9 Modulates Its Oncogenic Partner Meis1 To Influence Normal Hematopoiesis{triangledown}

Yu-Long Hu,1 Steve Fong,1 Christina Ferrell,2 Corey Largman,1* and Wei-Fang Shen1*

Department of Medicine, Department of Veterans Affairs Medical Center and University of California, San Francisco, California,1 Molecular Core Facility, Department of Veterans Affairs Medical Center, San Francisco, California2

Received 26 April 2009/ Returned for modification 8 June 2009/ Accepted 4 July 2009

While investigating the mechanism of action of the HOXA9 protein, we serendipitously identified Meis1 as a HOXA9 regulatory target. Since HOXA9 and MEIS1 play key developmental roles, are cooperating DNA binding proteins and leukemic oncoproteins, and are important for normal hematopoiesis, the regulation of Meis1 by its partner protein is of interest. Loss of Hoxa9 caused downregulation of the Meis1 mRNA and protein, while forced HOXA9 expression upregulated Meis1. Hoxa9 and Meis1 expression was correlated in hematopoietic progenitors and acute leukemias. Meis1+/– Hoxa9–/– deficient mice, generated to test HOXA9 regulation of endogenous Meis1, were small and had reduced bone marrow Meis1 mRNA and significant defects in fluorescence-activated cell sorting-enumerated monocytes, mature and pre/pro-B cells, and functional B-cell progenitors. These data indicate that HOXA9 modulates Meis1 during normal murine hematopoiesis. Chromatin immunoprecipitation analysis did not reveal direct binding of HOXA9 to Meis1 promoter/enhancer regions. However, Creb1 and Pknox1, whose protein products have previously been reported to induce Meis1, were shown to be direct targets of HOXA9. Loss of Hoxa9 resulted in a decrease in Creb1 and Pknox1 mRNA, and forced expression of CREB1 in Hoxa9–/– bone marrow cells increased Meis1 mRNA almost as well as HOXA9, suggesting that CREB1 may mediate HOXA9 modulation of Meis1 expression.

* Corresponding author. Present address for Wei-Fang Shen: Department of Pathology, Box 0511, University of California, 513 Parnassus Ave., HSW-501, San Francisco, CA 94143. Phone: (415) 476-6194. Fax: (415) 514-3165. E-mail: wei-fang.shen{at}ucsf.edu. Present address for Corey Largman: UCSF School of Medicine, 467 Kentucky Ave., Berkeley, CA 94707. Phone: (510) 306-7304. Fax: (510) 525-8738. E-mail: clargman{at}gmail.com

{triangledown} Published ahead of print on 20 July 2009.

Molecular and Cellular Biology, September 2009, p. 5181-5192, Vol. 29, No. 18
0270-7306/09/$08.00+0     doi:10.1128/MCB.00545-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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