Reuben - CML

Question 1

Mechanism behind CML

Answer 1

• The c-abl gene, which is on Ch9, undergoes a reciprocal translocation, which puts it on the Philadelphia Chromosome, Ch22.
• In CML there is an abnormal RNA 8.5Kb
• The normal protein is a serine-threonine kinase but in CML the bcr/abl protein is a tyrosine kinase.
• While the normal c-abl is active in regulating cell growth, in the bcr/c-abl hybrid, the inhibitory portion of the gene is missing and therefore it could not be turned off when enough growth had taken place. They would continue to grow even in the absence of any stimulus from the outside. They were also insensitive to normal cell death signals (Bcl2). The bcr/c-abl hybrid is unable to enter the nucleus so it exerts its affect on the cytoskeletal proteins by not allowing them to prevent entrance of immmature cells into the circulation.
• In order for c-abl to be active it usually has to dimerize - it is a kinase. The translocation makes it easier for the kinases to dimerize.
• The mutation traps the c-bl/bcr hybrid in the cytoplasm.
• You should be able to see the mutation in any of the WBCs

Question 2

How do you treat CML?

Answer 2

• imatinib – a tyrosine kinase inhibitor. It inhibits binding of the substrate to its pocket in the tyrosine kinase.
• You can also try allogeneic Stem Cell Transplant but that is only used as a last resort because the results aren’t nearly as good as imatinib. It works best in chronic phase 1 using sibling donors.

Question 3

How do we measure the efficacy of a treatment?

Answer 3

In looking for MMR (minimal molecular remission), we use a RT-PCR and look for a decrease of 4-5 logs in abl1 transcripts over a standard in 12-18 months. Nowadays we can even measure a 5-6 log reduction. We can also achieve CCyR (complete cytogenic remission), which is not as good as MMR by looking for less of a decrease in abl1 transcript or by looking at FISH. There is also CHR (complete hematologic remission) where the patient has no symptoms but this is an even less of a reduction that the previous 2.

Question 4

CML

Answer 4

• Chronic Myelocytic Leukemia
• Causes fatigue, high WBC count, weightloss, splenomegaly
• Disease of middle aged people
• Usually gives you 4-5 years of no trouble before it hits you
• clonal disorderd proliferation of myeloid cells, especially granulocytes which hang around the blood, spleen, and liver
• 3 phases: 1) chronic 2) accelerated 3) blast
• part of a class of diseases called myeloproliferative disorders

Question 5

Splenomegaly and CML

Answer 5

Most commons physial finding in CML. Spleen size is correlated with peripheral blood granulocyte counts.

Question 6

One way to diagnose

Answer 6

You can look on a gel. You should see extra band at 310 or 385 bp in addition to the regular 808 bp.