0:00
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.
0:28
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.
