After Discovering the JAK2 Mutation: Next Steps in Developing Targeted Treatments for PV, ET and MF

An interview with D. Gary Gilliland, PhD, MD

Member, Medical Advisory Board, MPD Foundation
Professor of Medicine, Harvard Medical School
Investigator, Howard Hughes Medical Institute
Director, Leukemia Program, Dana-Farber/Harvard Cancer Center
Director, Cancer Stem Cell Program, Harvard Stem Cell Institute .

Positive Identification of the Causal Gene Mutation
How Gleevec Works
Why the Mutation Doesn't Always Show Up
Next Steps in Drug Development
Cooperation vs. Competition Among Researchers
How the MPD Community Can Help
Coming Opportunities to Participate in Clinical Trials
A Final Word of Caution


Dr. Gary Gilliland is a leader of the Boston team that published "Activating mutation in the tyrosine kinase JAK2 in polycythemia vera, essential thrombocythemia, and myeloid metaplasia with myelofibrosis" in Cancer Cell, Vol 7, Issue 4, 24 March 2005. The text of their paper is available free at

The news, in simple English, is the discovery of the genetic mutation that causes PV, ET and MF. The discovery was announced almost simultaneously by teams in the United Kingdom and France, and other groups are said to be close to publishing similar findings.

Dr. Gilliland talked to Robert Rosen, President of the MPD Foundation, and members of the MPD Foundation Board on April 5, 2005. Here is what Dr. Gilliland told us, with a few explanations added for clarity.

Positive Identification of the Causal Gene Mutation

We have identified the gene mutation we think is causal for these disorders. It is a tyrosine kinase enzyme called JAK2 or Janus kinase 2.

Kinases are Achilles heels for attacking tumor growth, as demonstrated by the way Gleevec turns off the kinase that causes Chronic Myelogenous Leukemia.

The body normally regulates cell production. In the MPDs, the on-off switch - the JAK2 tyrosine kinase - is stuck in the "on" position. If we can inhibit this one tyrosine kinase, we should be able to develop targeted treatments for all three disorders. Once you turn the switch off, the rest is relatively immaterial.

Of course, our work so far doesn't answer all the questions. We still don't understand how one mutation can cause three distinct diseases. We're working on answering that question now.

How Gleevec Works

Kinases act as stop and go signals. Tyrosine kinase switches mediate signals to the cells. The mutation turns the switch permanently on.

Kinases and cells get their energy from adenosine triphosphate (ATP). It acts just like a battery, and delivers energy to cells. Gleevec looks like ATP, but instead of energizing the Abl kinase responsible for CML, it turns it off.

We are still trying to determine the length of remission. Gleevec is a suppressant, not a cure. Patients have to take it every day. But adding other agents may yield a cure.

We think we can target the JAK2 mutation in just the same way.

Why the Mutation Doesn't Always Show Up

The mutation is its own best biomarker. If a patient has it, he has ET, PV or MF.

In our study, we found the mutation in 74% of PV patients. We strongly suspect that more sensitive tests will yield higher percentages.

The frequency in ET was 35%. We're pretty sure this underestimates the true frequency, because our DNA sequencing did not include platelet precursors, which are key to ET. We analyzed blood samples that volunteers sent in to us, using peripheral neutrophils, which are circulating white blood cells. To be more accurate, we have to analyze bone marrow aspirations, which we couldn't obtain for this study. We are now planning to look at ET patients willing to provide bone marrow samples.

The same applies to MF: It's hard to get bone marrow aspirate, and circulating cells may still be normal. Dr. Ayalew Tefferi at the Mayo Clinic in Rochester says that 50% of MF patients have the mutation. But we need to confirm that.

Next Steps in Drug Development

We're already working with a couple of large pharmaceutical companies. They think this is going to be an important product for them. And it will become more important as the population ages.

The pharmaceutical companies have libraries of potential compounds. We'll work with them on assay development. We know the best ways to screen compounds.

In order to get a new drug into clinical practice, we'll work with any and all pharmaceutical companies that want to get involved. We won't make any exclusive deals. After all, we know that only one in 10 new drugs gets through the pipeline. We want every large pharmaceutical company engaged and pursuing this. The more people trying to make this work, the higher the likelihood of success.

We provide the screens, they provide the compounds, we do the testing. We already have a murine (mouse) model of PV. We also have one for ET and a promising one for recapitulating MF. So we can test these compounds in our mouse model system. Then the promising ones go back to the companies, where they are touched up and entered into preclinical and clinical trials. Once the compounds pass preclinical toxicology studies, we work with the pharmaceutical companies to develop clinical protocols. We insist on being involved in protocol design.

Cooperation vs. Competition Among Researchers

We have contacted all the groups that have published papers on the JAK2 mutation and exchanged data with all of them. We have good relationships with many other investigators: Dr. Tefferri, Ron Hoffman at the University of Illinois at Chicago Cancer Center, Josef Prchal at the Myeloproliferative Disorders Consultation Clinic at Baylor College of Medicine.

We are also working with the MPD Consortium in seeking an NIH research grant. We'll add our mouse model systems as an argument to win the grant.

We're happy to work with anyone who shares our goal of getting more effective treatments out to MPD patients as soon as possible. By soon I mean within three years. I think we can do that.

How the MPD Community Can Help

If there was ever a time in the history of MPDs, if there was ever a shining star to show people, this is it. We have the gene mutation. We have a large population of MPD patients undergoing treatments that seem to suppress the symptoms more or less effectively, but some of the treatments are 40 years old. And they often cause nasty side effects. That's absurd.

We have a good opportunity to act now. The MPD Foundation should try to target the groups that you think are most likely to succeed, and where a grant can give them a jump-start.

I'm talking as a member of the MPD Foundation's Medical Advisory Board now, not as a researcher looking for a grant. Give researchers a specific target of getting a compound into clinical trails within three years, and see what kind of proposals they come up with. You need to find a nimble, fast group that knows where it is going.

You could support an individual lab with a grant of $100,000 - $200,000 a year for two to three years, or a grant for multiple centers working together for about $1.5 million a year.

Coming Opportunities to Participate in Clinical Trials

The Internet patient accrual strategy is thrilling. For this trial, we solicited volunteers through the Internet. Five hundred eighty six (586) patients expressed interest in the study, and 345 sent in biologic samples for testing. As we start to develop promising compounds, we will set up the widest clinical trials we can and make them geographically accessible to as large a population as we can. We basically want to make the trial accessible to anyone who can get on the Web. We already know the endpoints we need for FDA approval.

A Final Word of Caution

We're hoping to have something on the street in three years. That's how long it took to develop Super Gleevec, which is the second generation of that product. But maybe inhibiting JAK2 is bad for other reasons. We don't know. But it's almost unprecedented that there is just this one mutation. We need to hit the mutation, and ignore normal JAK2.

There's never been such an exciting time for MPD research.

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