Identification of a second mutation in the JAK2 pathway that causes several forms of chronic leukemia resistant to imatinib may lead to new drug therapies, according to an article published online July 18 by the Public Library of Science Medicine.

Yana Pikman, a Howard Hughes Medical Institute (HHMI) medical research fellow, and Ross L. Levine, a former HHMI medical research fellow, identified the new mutation. D. Gary Gilliland, PhD, an HHMI investigator at Brigham and Women’s Hospital and Harvard Medical School, is coauthor 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, polycythemia vera, and essential thrombocytosis.
JAK2 normally encodes a protein that helps control production of new blood cells. With mutation, JAK2’s growth-stimulating signal gets turned on permanently, causing overproduction of one or another type of blood cell. In different forms, the overabundant cells may be various kinds of white blood cells, platelets, or red blood cells.

Over time, overproduction disrupts the balance of cells in blood, impairs 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 is in 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. “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 research is under way to identify small molecules that might be effective in overcoming the damage caused by the mutations.

Imatinib works by targeting the Philadelphia chromosome, a mutation that does not exist in these three forms of chronic leukemia.

The first mutation in JAK2 stimulating the JAK-STAT pathway was discovered in 2005 by Gilliland and Levine, an instructor at Harvard Medical School and the senior author of the PLoS Medicine paper, and was also reported by several other laboratories in the United Kingdom, France, and Switzerland. That first mutation accounts for about half the patients who have the three sub-types of chronic leukemia that imatinib cannot control.

“But we had found a significant number of patients who didn’t have that mutation,” Levine said. “So this (new discovery) represents our first insight into the cases not attributable to the first mutation. It doesn’t explain all of them, but it tells us more about this whole family of disorders.” Gilliland said there probably are other mutations in the same pathway that explain additional cases of leukemia.