Most insights into the molecular mechanisms underlying transformation by the p 210BCR/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 CD341 cells. Adhesion of BCR/ ABL-transduced CD341 cells to fibronectin was decreased, but migration over fibronectin was enhanced compared with that of mock-transduced CD341 cells. Adhesion to fibronectin did not decrease the proliferation of BCR/ABL-transduced CD341 cells but decreased the proliferation of mock-transduced CD341 cells. This was associated with elevated levels of p27Kip in p 210BCR/ABL-expressing CD341 cells. In addition, the presence of p 210BCR/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 CD341 cells. Thus, the transduction of CD341 cells with the b3a2-BCR/ABL cDNA recreates most, if not all, phenotypic abnormalities seen in primary CML CD341 cells. This model should prove useful for the study of molecular mechanisms associated with the presence of p 210BCR/ABL in CML. (Blood. 2001;97:2406-2412).