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Genetics for MPNs 3.0

Genetics for MPNs 3.0: 

Unit Three:   Philadelphia Chromosome, BCR-ABL, Gleevec and Targeted Gene Therapy

Introduction: Chronic Myelogenous Leukemia is a rare disease and a myeloproliferative disorder.  In its chronic early stages, lasting about five years, there is a massive expansion of white blood cell production.  Its accelerated phase leads to a blast crisis in which survival is measured in just a few months.

Just a few years ago, we could only count on radiation, chemotherapy or the risky option of bone marrow transplant to extend our lives but death rates were high, life expectancy short, and treatment harsh.  With the debut of Imatinib (Gleevec) in 2001 all that has changed. Today CML is a manageable chronic disease with normal life expectancy. More than that, the discovery and deployment process of this drug has developed a new paradigm for the industry that will affect all of us with MPNs.

This is the Gleevec story.

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April 5, 2001 – the NEJM

For those of us with myeloproliferative neoplasms, there can scarcely be a more significant event than the scientific paper published in the April 5, 2001 New England Journal of Medicine.  The findings made the cover of Time Magazine and the drug described was so effective it gained FDA approval the following month… in record time!   We need to file a copy of this paper with our medical records, hang a copy on our walls.  The breakthrough announced in this momentous article is the modern era equivalent of Andrew Fleming’s introduction of penicillin to a world without antibiotics in 1928.  And it applies directly to myeloproliferative disorders.

Gene therapy and all the sophisticated machinery of biotechnology created a magic bullet so precise that it pierced the heart of a myeloproliferative cancer, a genetically caused disease. .

The electrifying NEJM  headline that kicked off all the international attention is not catchy and it’s not easy to read but it’s life-changing:   Activity of a Specific Inhibitor of the BCR-ABL Tyrosine Kinase in the Blast Crisis of Chronic Myeloid Leukemia and Acute Lymphoblastic Leukemia with the Philadelphia Chromosome.” 

            Here’s the full abstract: http://nejm.highwire.org/cgi/content/full/344/14/1038#T4   (Do print this out!)  And http://nejm.highwire.org/cgi/reprint/344/14/1038.pdf

This is the payoff for your hard work in the course, a pathway into the highly technical headline of the abstract.  Let’s take it one step at a time in this seven question quiz:.

1 .Activity of specific inhibitor means : ­­­­­­­­­­­­­­­­________________________(Hint: what’s the opposite of gene expression?)

2. BCR-ABL …(Unless you already know the answer, put this aside for a minute, lots of description below.)

3. Tyrosine is    (a) an amino acid    (b) a gene  (c) a protein  (d) a City in the Ancient Middle East

4. Kinase means: _______________________ (Hint, this is one of our vocabulary words. Think “kinetic.:  The suffix “ –ase”  means enzyme. Kinase is shorthand for phosphotransferase.)

5. Blast crisis means: ____________________ (Blast is shorthand for myeloblast and is one of the elements pathologists  look for in bone marrow biopsies,)

6. Leukemia is ______________

7. The Philadelphia chromosome. (You’ve heard of it, you may even know if you’re positive or negative for it… but why on earth is it called the Philadelphia chromosome and what does I have to do with BCR-ABL, whatever that is?)

By the end of today’s unit you should be able to come back and answer all these questions.  Let’s start, however, by lightening up  with our video song of the day:

http://www.youtube.com/watch?v=fa7cj__4Em0

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BCR-ABL and the Philadelphia Chromosome

The beginning of the story takes place in Philadelphia in 1960 when two scientists, Peter Nowell from University of Pennsylvania School of Mediicnie and David Hungerford from Fox Chase Cancer Center discovered an abnormality on chromosome 22 associated with CML. They believed the chromosome  anomaly — taking its name from the city where it was discovered —  was not simply associated with CML but was causative.

Dr. Janet Rowley of the University of Chicago using the new techniques of chromosome banding and  visualization was able to confirm their view: Translocation of genetic material.  She discovered a crucial segment of chromosome 22, in patients with CML, had broken off and moved to chromosome 9. Simultaneously a piece of chromosome 9, including a chunk of the cancer-causing Abelson gene – moved to the breakpoint on chromosome 22.  This genetic translocation created an oncogene located on chromosome 22  that carries the code for the BCR-ABL protein.  (The protein’s name is taken from the two areas fused,  the “Breakpoint Cluster Region” of chromosome 22 coupled with the ABL gene from chromosome 9).  Beyond coding a protein, BCR-ABL incorporates the ability of the ABL gene to build complex molecules by adding phosphate groups to one of the basic amino acids, tyrosine.  That gave the BCR-ABL fusion gene/protein all the power of a kinase as well.

Along with signal transmission and control of processes within the cell, protein kinases catalyze molecular actions by adding phosphates to substrates. Since the substrate in this case is tyrosine, the BCR-ABL protein is known as a tyrosine kinase.

Continuously active, without the requirement for signalling from messaging proteins, BCR-ABL speeds up cell division and inhibits DNA repair.  The very capability that provides its lethal power  — its action as a tyrosine kinase  — opened the path to block its  depredations,   What was needed was something to disable BCR-ABL by inhibiting  its kinase component.

Enter Gleevec.

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The Story of Gleevec the ultimate designer drug

This story is best told by the principal investigator responsible for driving thjis effort, Dr. Brian Druker. Here’s his 30 minute seminar, “Imatinib (Gleevec) a Targeted Cancer Therapy.”  It is essential viewing. http://www.youtube.com/watch?v=d6xU3bgBLIw&feature=channel

What follows are some notes to help place his comments in perspective.

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If we know the cause we can find the cure

 Consider the odds against producing an effective drug to combat chronic myelogenous leukemia.  The first problem is to find the cause.  Discovery of the Philadephia chromosome correlating with all cases of CML was a clue. Establishing the molecular process through which a piece of DNA carrying the genetic material for a cancer causing virus gets translocated and fused with another gene on a distant chromosome is another part of the process that would have been unthinkable not so long ago.  Once the cause of CML is established, the tyrosine kinase locked in the on position, next step is to turn it off.  Reach beyond the cellular level into the molecular processes governing interactions between genes and proteins and enzymes to short circuit this BCR-ABL kinase connection without affecting all other, nearly identical, biochemical activities or triggeirng a whole cascading series of undesirable biomolecular events?   And even if all this could be done in a test-tube or petri dish how could this technology be bio-engineered into a pill that would carry out this mission once swallowed and digested.   The miracle happened. A new era in drug design opened. And we have every good reason to expect new MPN drugs as the paradigm that created Imatanib is adopted in labs around the world.

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People behind Gleevec

Gleevec is the first in a new class of agents to selectively inhibit an enzyme responsible for the proliferation of cancer cells.  This inhibitor neutralizes the action of a specific oncogene responsible for chronic myeloid cancer. . While the development of Gleevec rests on the massive work done in the human genome project and the collaboration of teams of scientists and technicians, the contribution of three men is outstanding. For a capsule background here’s a New York Times Interview with  Brian Druker  http://www.nytimes.com/2009/11/03/science/03conv.html,. a close-up look at  Nicholas Lydon http://www.scienceheroes.com/index.php?option=com_content&view=article&id=379&Itemid=312 and Charles Sawyers http://www.mskcc.org/mskcc/html/72337.cfm

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Review

(1) Work your way through the April 2001 NEJM article to test your knowledge of terms and processes used in genetics and molecular biology.  Share your questions and observations with others in the seminar.

(2) Re-visit last week’s introduction to BCR-ABL and Gleevec on the DNA Applications page of the Cold Spring Harbor Lab website.  Click on “Genes and Medicine” and then “Drug Design” and motor on over to the Philadelphia chromosome www.dnai.org/d/index.html

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School’s out for vacation.  Back for summer school June 5, 2010  with  The Life Cycle of an RBC

 

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