Potential mechanisms underlying disease persistence (molecular refractoriness). (A) Kinase domain mutations that confer moderate resistance to imatinib. (B) BCR-ABL levels may be particularly high in the most primitive leukemic stem cells. (C) Inadequate intracellular levels of imatinib as a result of PGP expression. (D) Physiologic growth factor signaling or (E) integrin signals may maintain viability even with BCR-ABL kinase activity completely inhibited. (F) Quiescent (dormant) cells may be protected against imatinib. VLA-5 indicates very late activation antigen-5.