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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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HEMATOPOIESIS
HOXB6 overexpression 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. Jeffrey Lawrence
From the Department of Medicine, Veterans Affairs Medical Center, San Francisco, CA; Department of Medicine, University of California San Francisco Medical School, San Francisco, CA; Department of Laboratory Medicine, University of California San Francisco, San Francisco, CA; University of California San Francisco Comprehensive Cancer Center, San Francisco, CA; and Section of Hematology/Oncology, University of Chicago, Chicago, IL.
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 overexpressed in human acute myeloid leukemia (AML). To gain further insight into the role of HOXB6 in hematopoiesis, we overexpressed 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, pre–B-cell leukemia transcription factor-1 (PBX1). Additionally, we investigated the potential cooperative interaction with myeloid ecotropic viral integration site 1 homolog (MEIS1). In vivo, HOXB6 expanded HSCs and myeloid precursors while inhibiting erythropoiesis and lymphopoiesis. Overexpression of HOXB6 resulted in AML with a median latency of 223 days. Coexpression 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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