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Molecular and Cellular Biology, June 2003, p. 3872-3883, Vol. 23, No. 11
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.11.3872-3883.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Reduced Proliferative Capacity of Hematopoietic Stem Cells Deficient in Hoxb3 and Hoxb4

Jon Mar Björnsson,1 Nina Larsson,1 Ann C. M. Brun,1 Mattias Magnusson,1 Elisabet Andersson,1 Patrik Lundström,1 Jonas Larsson,1 Ewa Repetowska,1 Mats Ehinger,2 R. Keith Humphries,3,4 and Stefan Karlsson1*

Department of Molecular Medicine and Gene Therapy,1 Department of Pathology, Lund University Hospital, Lund, Sweden,2 Terry Fox Laboratory, British Columbia Cancer Agency,3 Department of Medicine, University of British Columbia, Vancouver, British Columbia V5Z 1L3, Canada4

Received 4 September 2002/ Returned for modification 18 November 2002/ Accepted 2 March 2003

Several homeobox transcription factors, such as HOXB3 and HOXB4, have been implicated in regulation of hematopoiesis. In support of this, studies show that overexpression of HOXB4 strongly enhances hematopoietic stem cell regeneration. Here we find that mice deficient in both Hoxb3 and Hoxb4 have defects in endogenous hematopoiesis with reduced cellularity in hematopoietic organs and diminished number of hematopoietic progenitors without perturbing lineage commitment. Analysis of embryonic day 14.5 fetal livers revealed a significant reduction in the hematopoietic stem cell pool, suggesting that the reduction in cellularity observed postnatally is due to insufficient expansion during fetal development. Primitive Lin- ScaI+ c-kit+ hematopoietic progenitors lacking Hoxb3 and Hoxb4 displayed impaired proliferative capacity in vitro. Similarly, in vivo repopulating studies of Hoxb3/Hoxb4-deficient hematopoietic cells resulted in lower repopulating capability compared to normal littermates. Since no defects in homing were observed, these results suggest a slower regeneration of mutant HSC. Furthermore, treatment with cytostatic drugs demonstrated slower cell cycle kinetics of hematopoietic stem cells deficient in Hoxb3 and Hoxb4, resulting in increased tolerance to antimitotic drugs. Collectively, these data suggest a direct physiological role of Hoxb4 and Hoxb3 in regulating stem cell regeneration and that these genes are required for maximal proliferative response.

* Corresponding author. Mailing address: Molecular Medicine and Gene Therapy, Lund University Hospital, BMC A12, 221 84 Lund, Sweden. Phone: 46-46-2220577. Fax: 46-46-2220568. E-mail: stefan.karlsson{at}molmed.lu.se.

Molecular and Cellular Biology, June 2003, p. 3872-3883, Vol. 23, No. 11
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.11.3872-3883.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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