CML: genetic paradigm of targeted therapy 2

Published on September 30, 2015   35 min

A selection of talks on Cell Biology

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MICHAEL DEININGER: Hello, this is Dr. Michael Deininger. I'm the division chief for Hematology and Hematologic Malignancies at the University of Utah, Huntsman Cancer Institute. We continue our discussion of chronic myeloid leukemia, or CML. The second part of the presentation will cover topics of imatinib resistance, second and third generation tyrosine kinase inhibitors, and minimal residual disease in CML.
Now, let's look at the question of imatinib resistance. This Western blot shows you cells from a CML patient, analyzed for phosphorylation of CrkL, which is a substrate of BCR. The lower band in these Western blots is the non-phosphorylated form and the upper band is the phosphorylated form. What you predict with tyrosine kinase inhibitor is that the upper band will disappear completely, because only the non-phosphorylated protein will remain. However, if you look at the middle panel, even in the presence of 1 micromole of imatinib, the phosphorylation is completely preserved. That indicates that BCR-ABL signaling has been reactivated at the time of this resistance development. And in this particular patient, that turned out to be due to a mutation in the BCR-ABL kinase domain. In contrast, if you look at the right slide, the situation is very different. Despite the resistance, clinically there is a complete predominance of the non-phosphorylated form of CrkL, indicating that BCR-ABL kinase activity remains suppressed, and yet the disease has become resistant, suggesting that another pathway has been activated to replace BCR-ABL.