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MICHAEL DEININGER: Hello,
I'm Michael Deininger.
I'm the chief of the
Division of Hematology
Malignancies at the University
of Utah, Huntsman Cancer Institute.
Today, we're going to talk about
chronic myeloid leukemia, or CML,
genetic paradigm of targeted therapy.
The first part of the presentation
will focus on the biology of CML,
the Philadelphia chromosome, and
the development of Imatinib
as the first targeted agent
tyrosine kinase inhibitor for CML.
The story of chronic
myeloid leukemia, or CML,
starts in the middle
of the 19th century.
There were three eminent
physicians making major contributions.
Alfred Donné, in Paris, was probably
the first to recognize leukemia
also under the microscope.
John Bennet, in Edinburgh, was
the first to see a case of CML
and describe it.
Bennet thought that the case was
actually due to an infection,
because there was a 'separation
of the spleen', as he called it.
And just a few weeks later,
Rudolf Virchow, in Berlin,
described a similar case, but he
recognized the neoplastic nature
of the disease.
This is a timeline of CML.
As I already mentioned, the story
goes back to the mid 19th century.
The next decades see the
realization that leukemia
originates from the bone marrow.
Then in 1960, Nowell
and Hungerford described
the Philadelphia chromosome as an
abnormally small chromosome 22.
This was a seminal
discovery, as it the first
proof that cancer
is the problem, not
the DNA, and not the protein.
The next few years see the
realization that the Philadelphia
chromosome is the product
of a translocation
between chromosomes 9 and 22.
And subsequently, the identification
of the translocation partners,
BCR and ABL1.
In 1990, a mouse model was
described that reproduced
essential disease features.
Therapy developed slowly.
in 1975, was the first therapy
to induce long term remission.
But a decade later,
interferon alpha was described
as the first drug treatment
that was effective, at least
in a minority of the patients.
First, it was recognized that
tyrosine kinase activity of BCR-ABL
was essential for the disease
pathogenesis, and based on that,
inhibitors were developed.
In 1998, phase one
trials started testing
Imatinib in patients with CML.
Then over the subsequent years,
we see the rapid evolution
that is additional
tyrosine kinase inhibitors.
And this progress essentially
turned CML from a fatal disease
into a chronic ailment that can
successfully be handled with drugs.