Potential mechanisms of disease persistence on imatinib therapy.
(a) Enhanced drug efflux by ABCG2 (ATPase-binding cassette G2) and/or other transporters (green).
(
BCR-ABL target amplification by increased BCR-ABL transcript levels or gene amplification; insufficient concentration of inhibitor to completely shutdown kinase activity.
© BCR-ABL kinase domain mutations renderpersistent cells insensitive to imatinib.
(d) Protection within bone marrow microenvironment; stromal cells surround persistent cells.
(e) Quiescent, noncycling cells in deep G0 are impervious to the pro-apoptotic effects of imatinib.
(f) BCR-ABL is efficiently targeted, but BCR-ABL kinase activity is
dispensable for persistent cell survival.
