Childhood leukemia worsened by genetic mutations

Defects in JAK genes linked to higher relapse rate

DENVER — Mutations in any of three genes in the JAK family render a common childhood leukemia especially dangerous, researchers reported April 21 at a meeting of the American Association for Cancer Research. The finding may help doctors identify children at high risk of relapse and could ultimately offer a target for drug development, scientists say.

Acute lymphoblastic leukemia, or ALL, is the most common childhood leukemia. In this cancer, immature white blood cells multiply out of control and crowd out healthy blood cells. This causes anemia, weakens the immune system’s defense against infection and slows healing. 

ALL is treatable with chemotherapy, radiation or bone marrow transplants. In about 80 percent of childhood patients, these early regimens successfully knock out the cancer. But the other patients relapse and face poor prospects. Past research has indicated that genetic variability among people may explain why some patients fare poorly despite getting standard ALL treatment.

In the new study, researchers identified 187 children with ALL who had especially high white blood cell counts, suggesting they faced a high risk of relapse despite initial treatment. The patients lacked any known genetic defects that have been shown to make leukemia patients vulnerable to relapse, says study coauthor Charles Mullighan, a pathologist and hematologist at St. Jude Children’s Research Hospital in Memphis.

Genetic analysis of blood samples obtained from these children revealed that 11 percent — 20 kids — had a mutation in JAK1, JAK2 or JAK3. Overfour years, the relapse rate associated with a JAK mutation was 70 percent, compared with a 23 percent rate in the children who didn’t harbor a JAK mutation.

“This suggests that these mutations are a new target in this subtype of leukemia,” Mullighan says.

JAK is short for Janus kinase. The JAK genes encode kinase enzymes, which are instrumental in regulating cell functions such as proliferation and survival. JAK mutations seem to make cancers more aggressive, and therefore more likely to recur, by revving up the genes, resulting in the cell proliferation seen in these blood cancers. The manner in which that occurs is still being deciphered.

Meanwhile, pharmaceutical companies are working on JAK inhibitors that would dampen the genes’ signaling, but that testing is still in early stages.

JAK mutations have cropped up in other diseases, including a blood cancer called multiple myeloma and in Down syndrome. This study expands the range of diseases for which JAK mutations are implicated, the study authors note.

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