International MPN News, Science & Opinion

Fiddling with MPNs
– A cautionary tale

For us, much of the excitement generated by last week’s American Society of Clinical Oncology meeting in Chicago came from Incyte’s announcement of ruxolitinib likely fast tracking its way into our medicine cabinets. The successful clinical trials of this JAK2 inhibitor is indeed good news, another step forward in controlling deadly myelofibrosis. But we probably need to hold off the celebrations for a while at least.

And to suggest one reason why, a true story:

I’m not much of a fiddler. I started too late in life to get really good and I’m probably a little tone deaf to boot. Still, I do it all the time. To coax chords and melodies out of a wood box and metal strings using just a bow strung with hair, to make music, continues to strike me as near miraculous.

It’s not the kind of experience you would want to inflict on an audience. Anyone listening to the caterwauling cacophony that passes for my rendition of Blackberry Blossom would know the problem is not with the fiddle… but with the fiddler.

So what’s that got to do with myeloproliferative neoplasms?
Our MPNs are not only rare but the source of our diseases is shrouded in the deepest darkness. Our blood producing factory is encased in a sepulcher of bone in the recesses of our bodies. And though our physicians have names for the several ways our particular chaotic blood production manifests, they’re only imperfect descriptions of elaborate, complex and dynamic biochemical processes that take place far from our view.

It has been 40 years since Janet Rowley discovered the first cancer causing chromosome translocation responsible for acute myeloid leukemia. But until very recently we had almost no certain knowledge of the intricate workings of the deeper genetic anomalies associated with our myeloproliferative diseases. As Brian Druker showed in spearheading the development of imatinib for CML, chronic myeloid leukemias, by targeting those processes, gene therapy can not only alleviate the symptoms of our MPN, but alter its course.

Back to the fiddle. You can call what I do fiddling. It’s a description of the process, something I do on a fiddle, something observable, nameable. The resultant sound, frequently off-key to the accompaniment of strings screeching and gasping, is slowly improving. Practicing is key but small improvements can be made by introducing a shoulder rest, putting on new strings, applying rosin to the bow.

So too with our MPNs. Research scientists and clinicians are slowly developing drugs that improve our performance, our life quality, our length of days. It is wonderful and worthy of celebration. The fiddling improves but in many cases the fiddler, alas, remains tone deaf and rickety and might soon relapse back to his evil ways.

Myeloproliferative neoplasms are diseases characterized by excessive production of one or more blood lines. The result can be what we call ET or PV MF or the acute leukemias. The result can be minimal, or disabling or death.

Finding the causes of that excessive production, shedding a bright light into the deep darkness within the double genetic helix that encodes our MPNs, is a necessary first step in turning off the switches that spew out mutant blood-producing clones.

Some of us, healthy and young enough, have another alternative. We can fire the molecular crew producing this mutated blood and bring in another outside workforce from another, more fortunate, body. That is, hire a new fiddle section. While risky, this process of stem cell transplant can work. The fact that it does only proves the point that we’ve recognized for some time. The source of our MPNs is in the coding of our blood-producing stems cells, the hematopoietic stem cells, HSCs.

To fully recapture their harmonious interaction with the stew of enzymes and proteins buzzing around their world and restore the sweet music of our bloody marrow, we have to look not to the result of the disorder, the mutant cell — for example the JAK2V617F mutation — but the fiddler himself, the force driving our HSCs cells to play the tune to which we dance.

We’re getting there.

Allegro ma non troppo

© Zhenya Senyak and MPNforum.com, 2011. Unauthorized use and/or duplication of this material without express and written permission from this blog’s author and/or owner is strictly prohibited. Excerpts and links may be used, provided that full and clear credit is given to Zhenya Senyak and MPNforum.com with appropriate and specific direction to the original content.

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