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Blood, 15 February 2005, Vol. 105, No. 4, pp. 1456-1466.
Prepublished online as a Blood First Edition Paper on November 2, 2004; DOI 10.1182/blood-2004-04-1583.
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Submitted April 28, 2004
Accepted October 7, 2004
HOXB6 over-expression in murine bone marrow immortalizes a myelomonocytic precursor in vitro and causes hematopoietic stem cell expansion and acute myeloid leukemia in vivo
Neal A Fischbach*, Sofia Rozenfeld, Weifang Shen, Stephen Fong, Daniel Chrobak, David Ginzinger, Scott C Kogan, Archana Radhakrishnan, Michelle M Le Beau, Corey Largman, and H J Lawrence
Department of Medicine, Veterans Affairs Medical Center, San Francisco, CA, USA; Department of Medicine, University of California San Francisco Medical School, San Francisco, CA, USA; University of California Comprehensive Cancer Center, San Francisco, CA, USA
Department of Medicine, Veterans Affairs Medical Center, San Francisco, CA, USA
Advanced Scientific Applications, Applied Biosystems, Foster City, CA, USA
Department of Laboratory Medicine, University of California San Francisco, San Francisco, CA, USA; University of California Comprehensive Cancer Center, San Francisco, CA, USA
Section of Hematology/Oncology, University of Chicago, Chicago, IL, USA
Department of Medicine, Veterans Affairs Medical Center, San Francisco, CA, USA; University of California Comprehensive Cancer Center, San Francisco, CA, USA
* Corresponding author; email: fischba{at}itsa.ucsf.edu.
The HOX family of homeobox genes plays an important role in normal and malignant hematopoiesis. Dysregulated HOX gene expression profoundly effects the proliferation and differentiation of hematopoietic stem cells (HSCs) and committed progenitors, and aberrant activation of HOX genes is a common event in human myeloid leukemia. HOXB6 is frequently over-expressed in human acute myeloid leukemia (AML). To gain further insight into the role of HOXB6 in hematopoiesis, we over-expressed HOXB6 in murine bone marrow using retrovirus-mediated gene transfer. We also explored structure-function relationships using mutant HOXB6 proteins unable to bind to DNA or a key HOX binding partner, PBX1. Additionally, we investigated the potential cooperative interaction with MEIS1. In vivo, HOXB6 expanded HSCs and myeloid precursors, while inhibiting erythropoiesis and lymphopoiesis. Over-expression of HOXB6 resulted in AML with a median latency of 219 days. Co-expression of MEIS1 dramatically shortened the onset of AML. Cytogenetic analysis of a subset of HOXB6-induced AMLs revealed recurrent deletions of chromosome bands 2D-E4, a region frequently deleted in HOXA9-induced AMLs. In vitro, HOXB6 immortalized a factor-dependent myelomonocytic precursor capable of granulocytic and monocytic differentiation. These biologic effects of HOXB6 were largely dependent on DNA binding, but independent of direct interaction with PBX1.
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