title: Overexpression of the myeloid leukemia-associated Hoxa9 gene in bone marrow cells induces stem cell expansion.
abstract: Cytogenetic, genetic, and functional studies have demonstrated a direct link between deregulated Hoxa9 expression and acute myeloid leukemia (AML). Hoxa9 overexpression in mouse bone marrow cells invariably leads to AML within 3 to 10 months, suggesting the requirement for additional genetic events prior to AML. To gain further insight into how Hoxa9 affects hematopoietic development at the preleukemic stage, we have engineered its overexpression (1) in hematopoietic stem cells using retrovirus-mediated gene transfer and generated bone marrow transplantation chimeras and (2) in lymphoid cells using transgenic mice. Compared with controls, recipients of Hoxa9-transduced cells had an about 15-fold increase in transplantable lymphomyeloid long-term repopulating cells, indicating the capacity for this oncogene to confer a growth advantage to hematopoietic stem cells. In addition, overexpression of Hoxa9 in more mature cells enhanced granulopoiesis and partially blocked B lymphopoiesis at the pre-B-cell stage but had no detectable effect on T lymphoid development. Interestingly, despite specifically directing high expression of Hoxa9 in T and B lymphoid lineages, none of the Hoxa9 transgenic mice developed lymphoid malignancies for the observation period of more than 18 months.
authors.affiliation: Laboratory of Molecular Genetics of Hemopoietic Stem Cells, Clinical Research Institute of Montréal, Québec, Canada.
authors.forename: Unnur
authors.initials: U
authors.lastname: Thorsteinsdottir
authors.forename: Aline
authors.initials: A
authors.lastname: Mamo
authors.forename: Evert
authors.initials: E
authors.lastname: Kroon
authors.forename: Lori
authors.initials: L
authors.lastname: Jerome
authors.forename: Janet
authors.initials: J
authors.lastname: Bijl
authors.forename: H Jeffrey
authors.initials: HJ
authors.lastname: Lawrence
authors.forename: Keith
authors.initials: K
authors.lastname: Humphries
authors.forename: Guy
authors.initials: G
authors.lastname: Sauvageau
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000473:pathology; D001854:Bone Marrow Cells / Q000378:metabolism* / Q000473:pathology; D002452:Cell Count; D002455:Cell Division; D015870:Gene Expression; D005786:Gene Expression Regulation; D006098:Granulocytes; D006410:Hematopoiesis; D006412:Hematopoietic Stem Cells / Q000378:metabolism* / Q000473:pathology; D018398:Homeodomain Proteins / Q000235:genetics*; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000473:pathology; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009363:Neoplasm Proteins / Q000235:genetics*; D012190:Retroviridae / Q000235:genetics; D013601:T-Lymphocytes / Q000473:pathology; D014162:Transfection; D018183:Transplantation Chimera
chemical_list: D018398:Homeodomain Proteins; D009363:Neoplasm Proteins; C097899:homeobox protein HOXA9