9.10.07

A tyrosine kinase inhibitor for a Toronto maple leaf

Jason Blake, a top-notch hockey player currently playing for the Toronto Maple Leafs (suck it, Ottawa), has been diagnosed with chronic myelogenous leukemia (CML). CML is a hematological stem cell disorder (i.e. problem involving the cells in bone marrow from which mature blood cells develop) that involves uncontrolled proliferation (i.e. cancer) of myeloid cells (including all white blood cells except lymphocytes, and the precursors from which they are produced). CML is bad news because it means that the bone marrow is making tonnes of useless cancer cells while neglecting the production of useful blood cells, particularly white blood cells that are an important component of the immune system.

CML, if untreated, typically progresses through three phases. The initial chronic phase, which Blake is in right now, can last for months or even years and usually features either mild symptoms such as fatigue or else is asymptomatic. So for now Blake can keep on scoring goals (ahem, make that start scoring goals) for the most annoying team in the NHL. If drugs aren't given or don't work, the chronic phase eventually graduates to an accelerated phase, at which point things start going downhill as the cancer cells get better at dividing and avoiding apoptosis (staying alive). The final phase is called a blast crisis, at which point the leukemia is said to be acute (rapid proliferation of cancer cells and near-total shutdown of normal blood cell production). It's usually fatal. Thus the crisis bit.

CML, like a small number of cancers, is the result of a specific genetic defect. People with CML have an abnormally small chromosome called the Philadelphia chromosome in their myeloid cells. This chromosome, boringly named after the city in which it was discovered, is the result of a type of mutation called a chromosomal translocation, in which the long arms of chromosomes 9 and 22 break apart and trade places. This results in two genes, BCR and c-ABL, getting stuck together as a fusion gene.

Small digression time. Tyrosine kinases are a class of phosphorylating enzymes (proteins that catalyze reactions) that are involved in the regulation of cellular growth and differentiation. In other words, they can turn on and off the signal pathways that make cells divide like crazy and change from stem cells into mature cells.

Now, c-ABL encodes a tyrosine kinase. As a result, the BCR-ABL fusion gene also encodes a tyrosine kinase, albeit one that is completely wonkified (not a word). It is permanently set to turn on cell division and turn off the proper differentiation of stem cells into mature cells. This results in cancer, specifically CML.

Although it has not been stated explicitly, Blake is likely taking a rad new drug called imatinib (Gleevec, Glivec). Back in the day, when it was still under development, it was called STI-571. Anyway, imatinib is the first member of a brand spankin' new class of anticancer drugs, the tyrosine kinase inhibitors. Most anticancer drugs are cytotoxic agents intended to selectively kill enough cancer cells that your immune system can mop up the remainder. CML has proven to be tough to treat with typical anticancer drugs, which is why we have imatinib. Imatinib and other tyrosine kinase inhibitors are neat because their primary action is not to kill cancer cells, but rather to suppress their growth by selectively inhibiting the tyrosine kinases responsible for their existence. Imatinib is particularly good at shutting down BCR-Abl, making it a near-miracle drug for those with CML. So Blake should be good to go, now the Leafs just have to make it to the playoffs. Wish they had a miracle drug for that.

Remember that discount drugs can be easily found online, so don't delay on getting your hands on some Viagra, which can do more than you think, or cheap hoodia, to help you lose a couple of pounds by making you think that you are full when you're not.

- Hunter T. Treatment for chronic myelogenous leukemia: the long road to imatinib. J Clin Invest. 2007 Aug;117(8):2036-43. Review.
- Koretzky GA. The legacy of the Philadelphia chromosome. J Clin Invest. 2007 Aug;117(8):2030-2. Review.
- http://en.wikipedia.org/wiki/Imatinib

2 chemically inspired comments:

d_orbital said...

Wow, I had no idea he had CML. I attended college at the same time as him and watched him play all the time (I could get in that is).

Isn't he a little young for CML? I thought age 50 was when the high risk kicked in.

Chris said...

Thanks for commenting!

To quote the venerable Wikipedia:

"CML occurs in all age groups, but most commonly in the middle-aged and elderly".

So yeah, he's a bit young, but it's not way out of the ordinary as far as CML goes.