Chronic myeloid leukemia (CML) is a clonal myeloproliferative disorder of the hematopoietic stem cells and accounts for 15% of leukemias in adults. The translocation-related (9; 22)-protein product is the Bcr-Abl fusion protein, which displays a constitutive tyrosine kinase activity.
Imatinib, a selective inhibitor of Abl kinase is approved for the treatment of chronic phase CML (CP) and for Philadelphia-Chromosome positive (Ph+) acute lymphatic leukemia (ALL). Unfortunately, the clinical efficacy of Imatinib continuously decreases with the advancement of the disease. Blast crisis CML or Ph+ ALL patients benefit from the treatment with tyrosine kinase inhibitors only temporarily or not at all. Acquired resistance in the chronic phase (CP) is mostly due to the acquisition of point mutations in Bcr-Abl by either reducing the affinity of the kinase domain for this ATP-competitor, or stabilizing the active conformation of the Abl kinase domain. In addition, drug resistance is encounter during the blast crisis (BC) which mainly mediated by Bcr-Abl independent alterations.
Second generation inhibitors of Abl kinase activity such as Nilotinib and Dasatinib and recently Ponatinib reported to overcome Bcr-Abl acquired resistance. However, all Abl kinase inhibitors failed to overcome drug resistance during blast crisis (BC).
In an attempt to develop a model system that resemble CML blast crisis, we introduced EMT modulator Snail and Twist1 into Ph-positive leukemia cells. Interestingly, overexpression of Snail, but not Twist1, confers drug resistance to Abl kinase inhibitors (AKIs). For example, sensitivity of K562/Snail to Dasatinib was reduced by more than 600 fold when compared to sensitivity of parental K562 cells. Moreover, AKIs fail to inhibit Bcr-Abl auto-phosphorylation and other down-stream regulators such as STAT5a. Interestingly, over-expression of Snail in Ph-positive leukemia cells confers sensitivity to the nucleoside analog, Gemcitabine. Mechanisms responsible for drug resistance to AKI and collateral sensitivity to Gemcitabine will be presented.
