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1. Genetics and management of inherited cancer predisposition 1
- Prof. Joshua Schiffman
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2. Genetics and management of inherited cancer predisposition 2
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3. The cytogenetics of childhood acute leukemia
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4. Chromosome translocations and cancer
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5. Acute myeloid leukemia: genetics, prognosis and treatments
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6. Genetic abnormalities in acute lymphoblastic leukemia
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7. Molecular genetics of non-Hodgkin lymphoma
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8. Genetics of breast and ovarian cancer
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9. The genetics and genomics of familial renal carcinoma
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10. Genomics of lung cancer
- Prof. Ramaswamy Govindan
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11. The genetics of glioblastoma
- Dr. Hai Yan
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12. Genetics of tumor metastasis 1
- Prof. Robert Weinberg
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13. Genetics of tumor metastasis 2
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14. CML: genetic paradigm of targeted therapy 1
- Prof. Michael W. Deininger
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15. CML: genetic paradigm of targeted therapy 2
- Prof. Michael W. Deininger
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16. The non-coding RNA revolution in the cancer society
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17. Role of molecular markers in guiding therapy in cancer
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18. Functional cancer genomics
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19. Pharmacogenomics in cancer therapy
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Printable Handouts
Navigable Slide Index
- Introduction
- Leukemia pioneers
- A time line of chronic myeloid leukemia (CML)
- Chronic myeloid leukemia – an average case
- Chronic myeloid leukemia: Blood smear
- Typical clinical findings of CML
- CML - clinical basics
- The Philadelphia chromosome
- The juxtaposition of BCR and ABL1
- Genomic anatomy of BCR-ABL1
- CML: target cells for transformation
- ABL1, BCR-ABL1, SRC
- Kinase activation in BCR-ABL1: phosphorylation 1
- Kinase activation in BCR-ABL1: phosphorylation 2
- BCL pathways
- CML phases
- Mechanisms of blastic transformation
- BCR-ABL1 kinase activity & CML pathogenesis
- CML: ideal for targeted therapy
- Imatinib greatly improved survival in CML
- Sensitivity of monitoring strategies
- IRIS study: patient status at 72 months
- Annual events on first-line Imatinib (IRIS study)
- Overall survival on first-line Imatinib
- Survival after imatinib is similar to the general pop.
- Less encouraging data for imatinib treatment
- Remaining challenges
Topics Covered
- Typical clinical findings and phases of chronic myeloid leukaemia (CML)
- Philadelphia chromosome (juxtaposition & genomic anatomy BCR-ABL1)
- Target cells for transformation
- Molecular driver for pathogenesis (BCR-ABL1 tyrosine kinase)
- Imatinib (inhibitor of BCR-ABL1)
Links
Series:
Categories:
Therapeutic Areas:
Talk Citation
Deininger, M.W. (2015, September 30). CML: genetic paradigm of targeted therapy 1 [Video file]. In The Biomedical & Life Sciences Collection, Henry Stewart Talks. Retrieved December 3, 2024, from https://doi.org/10.69645/OSYK2864.Export Citation (RIS)
Publication History
Financial Disclosures
- Prof. Michael W. Deininger has not informed HSTalks of any commercial/financial relationship that it is appropriate to disclose.
CML: genetic paradigm of targeted therapy 1
Published on September 30, 2015
24 min
A selection of talks on Cell Biology
Transcript
Please wait while the transcript is being prepared...
0:00
MICHAEL DEININGER: Hello,
I'm Michael Deininger.
I'm the chief of the
Division of Hematology
and Hematologic
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.
0:33
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.
1:13
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.
allogeneic transplant,
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.
Then, therapeutic
progress accelerates.
First, it was recognized that
tyrosine kinase activity of BCR-ABL
was essential for the disease
pathogenesis, and based on that,
tyrosine kinase
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
of additional
therapeutic modalities,
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.