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 th e p210(BCR/ABL) oncoprotein are derived from studies in which BCR/ABL cDNA was introduced into hematopoietic or fibroblast cell lines. However, such c ell line models may not represent all the features of chronic myelogenous l eukemia (CML) caused by additional genetic abnormalities and differences in the biology of cell lines compared with primary hematopoietic progenitor a nd stem cells. A primary human hematopoietic progenitor cell model for CML was developed by the transduction of b3a2 BCR/ABL cDNA in normal CD34(+) ce lls. Adhesion of BCR/ ABL-transduced CD34(+) cells to fibronectin was decre ased, but migration over fibronectin was enhanced compared with that of moc k-transduced CD34(+) cells. Adhesion to fibronectin did not decrease the pr oliferation of BCR/ABL-transduced CD34(+) cells but decreased the prolifera tion of mock-transduced CD34(+) cells. This was associated with elevated le vels of p27(Kip) in p210(BCR/ABL)-expressing CD34(+) cells. In addition, th e presence of p210(BCR/ABL) delayed apoptosis after the withdrawal of cytok ines and serum. Finally, significantly more and larger myeloid colony-formi ng units grew from BCR/ABL than from mock-transduced CD34(+) cells. Thus, t he transduction of CD34(+) cells with the b3a2-BCR/ABL cDNA recreates most, if not all, phenotypic abnormalities seen in primary CML CD34(+) cells. Th is model should prove useful for the study of molecular mechanisms associat ed with the presence of p210(BCR/ABL) in CML. (Blood, 2001;97:2406-2412) (C ) 2001 by The American Society of Hematology.