Mutations Point the Way to New Leukemia Drugs

Researchers recently discovered that a mutation in the JAK2 gene is responsible for the majority of cases of three rare kinds of chronic leukemia, all of which are resistant to the leukemia drug Gleevec. The new study identifies a second mutation in the same pathway that can also cause the disease, leading researchers to think that drugs targeting JAK-STAT signaling should be effective against leukemias caused by either mutation.

In a study published July 18, 2006, in the online journal Public Library of Science Medicine, a team led by Yana Pikman, a Howard Hughes Medical Institute (HHMI) medical research fellow, and Ross L. Levine, a former HHMI medical research fellow, found a mutation in a gene called MPL in a subset of leukemias that lacked the more common JAK2 mutation. HHMI medical research fellows are medical students who compete for the opportunity to spend a year doing full-time research.

D. Gary Gilliland, an HHMI investigator at Brigham and Women's Hospital and Harvard Medical School, is co-author of the paper.

"We're excited about this finding because we hope to identify a common drug, an inhibitor of the JAK2 pathway, to treat patients with these types of leukemia," said Gilliland, who in 2005 worked with Levine to identify the JAK2 mutation responsible for most cases of myelofibrosis (MF), polycythemia vera (PV), and essential thrombocytosis (ET).

JAK2 normally encodes a protein that helps control the production of new blood cells. But when the gene is mutated, JAK2's growth-stimulating signal gets turned on permanently, causing overproduction of one or another type of blood cell. In different forms of the disease, the overabundant cells may be various kinds of white blood cells, platelets, or oxygen-carrying red blood cells.

Over time, this overproduction disrupts the balance of cells in the blood, hampers normal immune responses, overcrowds the bone marrow to make it dense and stiff, and forces blood formation to shift to the spleen and liver. Eventually those two organs become grossly enlarged; the end result is death.

Thus, the JAK2 pathway is an important player in leukemia. Levine, Pikman, and Gilliland's new work shows that the pathway can be activated without a mutation in the JAK2 gene itself. The new mutation they found lies in a gene called MPL. MPL encodes a receptor protein that sits on the surface of some blood cells and receives growth signals, communicating to JAK2 when a signal has arrived. Mutated MPL, however, constantly tells JAK2 to trigger growth - whether or not the appropriate signal has reached the cell. Thus, the end result is the same as that of a mutation that activates JAK2 directly: uncontrolled growth and an imbalance of blood cells.

"Now we have two targets that may be useful in the search for drug treatments to control chronic leukemia," said Pikman, lead author of the PLoS Medicine article and a student at Harvard Medical School. "This new mutation is interesting because when we express it in mice, they get a very similar disease, so it may be a good model for testing drugs against leukemia," Pikman added. She said a search is already under way to identify small molecules that might be effective in overcoming the damage caused by the mutations.