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Molecular and Cellular Biology, March 2004, p. 1907-1917, Vol. 24, No. 5
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.5.1907-1917.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Differential and Common Leukemogenic Potentials of Multiple NUP98-Hox Fusion Proteins Alone or with Meis1

Nicolas Pineault,1 Carolina Abramovich,1 Hideaki Ohta,1 and R. Keith Humphries1,2*

Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver V5Z 1L3,1 Department of Medicine, University of British Columbia, Vancouver V5Z 4E3, British Columbia, Canada2

Received 21 August 2003/ Returned for modification 22 October 2003/ Accepted 20 November 2003

NUP98-Hox fusion genes are newly identified oncogenes isolated in myeloid leukemias. Intriguingly, only Abd-B Hox genes have been reported as fusion partners, indicating that they may have unique overlapping leukemogenic properties. To address this hypothesis, we engineered novel NUP98 fusions with Hox genes not previously identified as fusion partners: the Abd-B-like gene HOXA10 and two Antennepedia-like genes, HOXB3 and HOXB4. Notably, NUP98-HOXA10 and NUP98-HOXB3 but not NUP98-HOXB4 induced leukemia in a murine transplant model, which is consistent with the reported leukemogenic potential ability of HOXA10 and HOXB3 but not HOXB4. Thus, the ability of Hox genes to induce leukemia as NUP98 fusion partners, although apparently redundant for Abd-B-like activity, is not restricted to this group, but rather is determined by the intrinsic leukemogenic potential of the Hox partner. We also show that the potent leukemogenic activity of Abd-B-like Hox genes is correlated with their strong ability to block hematopoietic differentiation. Conversely, coexpression of the Hox cofactor Meis1 alleviated the requirement of a strong intrinsic Hox-transforming potential to induce leukemia. Our results support a model in which many if not all Hox genes can be leukemogenic and point to striking functional overlap not previously appreciated, presumably reflecting common regulated pathways.

* Corresponding author. Mailing address: Terry Fox Laboratory, 601 West 10th Avenue, Vancouver, BC V5Z 1L3, Canada. Phone: (604) 877-6070, ext. 3095. Fax: (604) 877-0712. E-mail: khumphri{at}bccrc.ca.

Molecular and Cellular Biology, March 2004, p. 1907-1917, Vol. 24, No. 5
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.5.1907-1917.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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