title: HOXB6 overexpression in murine bone marrow immortalizes a myelomonocytic precursor in vitro and causes hematopoietic stem cell expansion and acute myeloid leukemia in vivo.
abstract: 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.
authors.affiliation: Department of Medicine, Veterans Affairs Medical Center, San Francisco, CA 94121, USA. fischba@itsa.ucsf.edu
authors.forename: Neal A
authors.initials: NA
authors.lastname: Fischbach
authors.forename: Sofia
authors.initials: S
authors.lastname: Rozenfeld
authors.forename: Weifang
authors.initials: W
authors.lastname: Shen
authors.forename: Stephen
authors.initials: S
authors.lastname: Fong
authors.forename: Daniel
authors.initials: D
authors.lastname: Chrobak
authors.forename: David
authors.initials: D
authors.lastname: Ginzinger
authors.forename: Scott C
authors.initials: SC
authors.lastname: Kogan
authors.forename: Archana
authors.initials: A
authors.lastname: Radhakrishnan
authors.forename: Michelle M
authors.initials: MM
authors.lastname: Le Beau
authors.forename: Corey
authors.initials: C
authors.lastname: Largman
authors.forename: H Jeffrey
authors.initials: HJ
authors.lastname: Lawrence
mesh_terms: D000208:Acute Disease; D000818:Animals; D001854:Bone Marrow Cells / Q000378:metabolism* / Q000473:pathology*; D002454:Cell Differentiation / Q000235:genetics; D002461:Cell Line, Transformed; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000473:pathology*; D004920:Erythropoiesis / Q000235:genetics; D005260:Female; D018398:Homeodomain Proteins / Q000096:biosynthesis* / Q000235:genetics* / Q000502:physiology; D007621:Karyotyping; D007951:Leukemia, Myeloid / Q000097:blood* / Q000235:genetics / Q000473:pathology; D038041:Lymphopoiesis / Q000235:genetics; D051379:Mice; D020297:Mice, Congenic; D008810:Mice, Inbred C57BL; D000075064:Myeloid Ecotropic Viral Integration Site 1 Protein; D023461:Myeloid Progenitor Cells / Q000378:metabolism* / Q000473:pathology*; D009363:Neoplasm Proteins / Q000502:physiology; D010641:Phenotype; D013997:Time Factors
chemical_list: D018398:Homeodomain Proteins; C490537:Hoxb6 protein, mouse; C000616391:MEIS1 protein, human; C000616392:Meis1 protein, mouse; D000075064:Myeloid Ecotropic Viral Integration Site 1 Protein; D009363:Neoplasm Proteins