The researchers discovered, in some high-risk ALL patients, that mutations in JAK appeared to work in concert with another mutation-in the gene IKZF1-which they had earlier found to underlie such cases.

"Our studies of these leukemia subtypes indicate that leukemia is not necessarily a single-cause disease," said Cheryl Willman, M.D., director and CEO of the University of New Mexico Cancer Research and Treatment Center and a co-senior author of the study. "A patient may have multiple different genetic lesions that target different cellular pathways to induce leukemia. Thus, it is very important to develop new therapies that target these specific mutations, and our discovery of JAK as target now allows us to begin to develop clinical trials with JAK inhibitors for children and adults with this form of disease."

In further studies, the researchers plan to identify mutations in kinase genes and other enzymes that underlie high-risk ALL, as well as explore how these abnormalities might work together to drive the cancers.

The discovery that mutations in JAK underlie some cases of high-risk ALL is enough to warrant clinical trials of inhibitory drugs to treat such cancers.

"JAK-inhibiting drugs are now moving into clinical trials for treatment of such adult myeloproliferative diseases as polycthemia vera, essential thrombocytosis and primary myelofibrosis," Downing said. "We expect that there will soon be initial clinical studies to assess the safety and effectiveness of these drugs in children with relapsed ALL in which JAK mutations have been identified within their leukemic cells."

Such studies would be coordinated by the COG, an international clinical trial cooperative group supported by the NCI.

stjude