The oncoprotein E2A-Pbx1a collaborates with Hoxa9 to acutely transform primary bone marrow cells.
A recurrent translocation between chromosome 1 (Pbx1) and 19 (E2A) leading to the expression of the E2A-Pbx1 fusion oncoprotein occurs in approximately 5 to 10% of acute leukemias in humans. It has been proposed that some of the oncogenic potential of E2A-Pbx1 could be mediated through heterocomplex formation with Hox proteins, which are also involved in human and mouse leukemias. To directly test this possibility, mouse bone marrow cells were engineered by retroviral gene transfer to overexpress E2A-Pbx1a together with Hoxa9. The results obtained demonstrated a strong synergistic interaction between E2A-Pbx1a and Hoxa9 in inducing growth factor-independent proliferation of transduced bone marrow cells in vitro and leukemic growth in vivo in only 39 +/- 2 days. The leukemic blasts which coexpress E2A-Pbx1a and Hoxa9 showed little differentiation and produced cytokines such as interleukin-3, granulocyte colony-stimulating factor, and Steel. Together, these studies demonstrate that the Hoxa9 and E2A-Pbx1a gene products collaborate to produce a highly aggressive acute leukemic disease.
Thorsteinsdottir
U
U
Laboratory of Molecular Genetics of Hemopoietic Stem Cells, Clinical Research Institute of Montréal, Montréal, Québec, Canada H2W 1R7.
Krosl
J
J
Kroon
E
E
Haman
A
A
Hoang
T
T
Sauvageau
G
G
D000818:Animals; D001854:Bone Marrow Cells / Q000473:pathology; D002455:Cell Division; D002471:Cell Transformation, Neoplastic; D015870:Gene Expression; D018014:Gene Transfer Techniques; D018398:Homeodomain Proteins / Q000235:genetics / Q000502:physiology*; D006801:Humans; D007942:Leukemia, Experimental / Q000235:genetics; D051379:Mice; D009368:Neoplasm Transplantation; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000502:physiology*; D014178:Translocation, Genetic
D018398:Homeodomain Proteins; D015514:Oncogene Proteins, Fusion; C097899:homeobox protein HOXA9; C089847:E2A-Pbx1 fusion protein