A model of human p210(bcr/ABL)-mediated chronic myelogenous leukemia by transduction of primary normal human CD34(+) cells with a BCR/ABL-containing retroviral vector.
Most insights into the molecular mechanisms underlying transformation by the p210(BCR/ABL) oncoprotein are derived from studies in which BCR/ABL cDNA was introduced into hematopoietic or fibroblast cell lines. However, such cell line models may not represent all the features of chronic myelogenous leukemia (CML) caused by additional genetic abnormalities and differences in the biology of cell lines compared with primary hematopoietic progenitor and stem cells. A primary human hematopoietic progenitor cell model for CML was developed by the transduction of b3a2 BCR/ABL cDNA in normal CD34(+) cells. Adhesion of BCR/ABL-transduced CD34(+) cells to fibronectin was decreased, but migration over fibronectin was enhanced compared with that of mock-transduced CD34(+) cells. Adhesion to fibronectin did not decrease the proliferation of BCR/ABL-transduced CD34(+) cells but decreased the proliferation of mock-transduced CD34(+) cells. This was associated with elevated levels of p27(Kip) in p210(BCR/ABL)-expressing CD34(+) cells. In addition, the presence of p210(BCR/ABL) delayed apoptosis after the withdrawal of cytokines and serum. Finally, significantly more and larger myeloid colony-forming units grew from BCR/ABL than from mock-transduced CD34(+) cells. Thus, the transduction of CD34(+) cells with the b3a2-BCR/ABL cDNA recreates most, if not all, phenotypic abnormalities seen in primary CML CD34(+) cells. This model should prove useful for the study of molecular mechanisms associated with the presence of p210(BCR/ABL) in CML.
Zhao
R C
RC
Department of Medicine, Stem Cell Institute, and Cancer Center, University of Minnesota, Minneapolis 55455, USA.
Jiang
Y
Y
Verfaillie
C M
CM
D018952:Antigens, CD34 / Q000032:analysis; D017209:Apoptosis; D018797:Cell Cycle Proteins; D002461:Cell Line, Transformed; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D002478:Cells, Cultured; D050760:Cyclin-Dependent Kinase Inhibitor p27; D018076:DNA, Complementary / Q000235:genetics; D005312:Fetal Blood / Q000166:cytology; D016044:Fusion Proteins, bcr-abl / Q000235:genetics* / Q000502:physiology; D005822:Genetic Vectors / Q000235:genetics; D006412:Hematopoietic Stem Cells / Q000473:pathology*; D006801:Humans; D008869:Microtubule-Associated Proteins / Q000096:biosynthesis; D009363:Neoplasm Proteins / Q000235:genetics* / Q000502:physiology; D009857:Oncogenes; D012190:Retroviridae / Q000235:genetics; D014162:Transfection; D025521:Tumor Suppressor Proteins
D018952:Antigens, CD34; D018797:Cell Cycle Proteins; D018076:DNA, Complementary; D008869:Microtubule-Associated Proteins; D009363:Neoplasm Proteins; D025521:Tumor Suppressor Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D016044:Fusion Proteins, bcr-abl