A working model depicting a link between BCR-ABL tyrosine kinase activity and the accumulation of secondary genetic and epigenetic changes in CML progenitors over time. Once a threshold (at top) of secondary molecular events is reached, hematopoietic differentiation is lost, resulting in blastic transformation. Drugs with no effect on BCR-ABL tyrosine kinase activity would be associated with an inevitable progression to blast crisis (black circles). Complete suppression of BCR-ABL (white circles) in CML stem cells might prevent blastic progression indefinitely, while incomplete suppression (gray shaded circles) due to ineffective drug delivery or BCR/ABL kinase domain mutations would only delay the accumulation of secondary events.