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Discovery of a new mutation in JAK2V617F negative myelofibrosis patients

By: Dr. Gary Gilliland, Harvard Medical School

Many patients with polycythemia vera (PV), essential thrombocythemia (ET) or myelofibrosis (MF) have the JAK2V617F mutation. This finding has reinvigorated and revolutionized research on these MPDs. We now understand that there is a cell growth pathway that is activated by the JAK2V617F mutations, call the JAK-STAT pathway. This pathway normally serves as an "on-off" switch to generate specific types of blood cells as needed. The JAK2V617F mutation locks the switch in the "on" position, and results in the overproduction of white cells, red cells and/or platelets that are present in MPD patients. Perhaps more importantly, the discovery of the JAK2V617F mutation has fostered an intensive ongoing search for JAK2 inhibitors that can be tested in clinical trials.

However, a significant proportion of MPD patients, in particular those with ET or MF, are JAK2V617F negative. Investigators supported by the MPD Alliance have recently made an exciting discovery of a new mutation in MF and ET patients that are JAK2V617F negative. Finding a new mutation against the backdrop of the extraordinary complexity of the human genome is more daunting searching for a needle in a haystack. However, investigators at Harvard Medical School and at the Mayo Clinic reasoned that the best place to begin the search would to screen components of the JAK-STAT pathway for mutations. They used robotics to perform high-throughput DNA sequence analysis of each of the genetic components of the pathway, including genes for cytokine receptors that bind to JAK2 and are the initial trigger for the "on" switch.

Using this strategy, they made an exciting new discovery: there is a mutation called W515L in the gene encoding the cytokine receptor MPL (also known as the thrombopoietin receptor) that is responsible for growth of blood cells that produce platelets. MPLW515L is present in ~5-10% of MF patients, and at a lower frequency in ET patients. These findings were recently published in the free online access journal PLoS Med by the Harvard group, and in the journal Blood by the Mayo Clinic group (see references below).

There are three important points that are highlighted by this work. First, this provides an important proof-of-principle that it should be possible, with further work, to ultimately identify all of the mutations that cause PV, ET or MF. Second, as for JAK2V617F, efforts are now focusing on developing inhibitors of MPLW515L that can be used in clinical trials. However, initial experiments indicate that JAK2 inhibitors are also effective, as might be predicted, in inhibiting the MPLW515L mutations, since MPL requires JAK2 for its activity. Third, the remarkably rapid pace of this discovery demonstrates the value of synergistic interactions between investigators that are supported by the MPD Alliance.

 

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