BCR-ABL-transduced human cord blood cells produce abnormal populations in immunodeficient mice.
In this study, we describe the successful use of a gene transfer approach to demonstrate the ability of forced BCR-ABL expression to deregulate the growth and differentiation of primitive naive human hematopoietic cells after their transplantation into immunodeficient mice. Human CD34+ cord blood cells were exposed to an MSCV retrovirus containing a BCR-ABL-IRES-GFP (P210) cassette and then injected immediately into sublethally irradiated nonobese diabetic-severe combined immunodeficiency (NOD/SCID) or NOD/SCID-beta2microglobulin-/- mice. P210- and control-transduced (GFP+) human hematopoietic cells were produced in the bone marrow of the mice at similar levels until termination of the experiments 5-6 months later. However, the P210-transduced cells produced a markedly different spectrum of progeny, with an increased ratio of myeloid to B-lymphoid cells and a frequently prolonged increase in erythroid and megakaryocytic cells. After 5 months, several of the mice transplanted with P210-transduced cells developed an increased WBC count and/or splenomegaly due to an expansion of the human GFP+ population. These findings demonstrate that forced expression of BCR-ABL in primitive transplantable human hematopoietic cells is sufficient to cause a rapid and persistent deregulation of their growth and differentiation in vivo with occasional evidence after several months of progression to an early stage of disease.
Chalandon
Y
Y
Terry Fox Laboratory, British Columbia Cancer Agency, University of British Columbia, Vancouver, BC, Canada.
Jiang
X
X
Christ
O
O
Loutet
S
S
Thanopoulou
E
E
Eaves
A
A
Eaves
C
C
D000818:Animals; D018952:Antigens, CD34 / Q000276:immunology; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D002455:Cell Division / Q000235:genetics / Q000276:immunology; D004195:Disease Models, Animal; D018450:Disease Progression; D005312:Fetal Blood / Q000166:cytology*; D016044:Fusion Proteins, bcr-abl / Q000235:genetics* / Q000276:immunology; D018014:Gene Transfer Techniques; D005822:Genetic Vectors / Q000235:genetics; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000276:immunology; D006801:Humans; D007942:Leukemia, Experimental; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008822:Mice, Transgenic; D009368:Neoplasm Transplantation
D018952:Antigens, CD34; D049452:Green Fluorescent Proteins; D016044:Fusion Proteins, bcr-abl