More gene mutations found in childhood leukemia
(13 May 2009: VIDYYA MEDICAL NEWS SERVICE) -- In January, researchers described a new subtype of acute lymphoblastic leukemia (ALL), the most common childhood cancer. Children with this subtype have alterations to a gene called IKAROS (or IZKF1) and a high risk of relapse. The researchers predicted that some cases would also involve mutations in protein kinase genes, which play a role in cell signaling and are commonly altered in cancer. New research now confirms that prediction.
A genetic analysis of 187 cases of high-risk childhood ALL by investigators with the Childhood Cancer TARGET Initiative has identified mutations in three members of the family of JAK kinase genes. The JAK mutations are thought to activate pathways involved in cell growth and proliferation. Such changes have also been implicated in other cancers, most notably in a group of blood cancers known as myeloproliferative disorders.
About 10 percent of the ALL cases had mutations in one of the three JAK genes. Some also involved changes to IKAROS, and these children had poor outcomes. More than 70 percent of children with both IKAROS and JAK mutations relapsed within 4 years, compared with 23 percent with neither alteration.
Drugs that inhibit overactive JAK kinase proteins are in development. Based on laboratory experiments, the researchers are hopeful that these agents might benefit patients with these mutations. In the lab, JAK mutations caused normal cells to become cancerous, while an experimental JAK inhibitor caused cells with the mutations to die.
The research team includes investigators from St. Jude Children's Research Hospital, the University of New Mexico Cancer Center, the Children's Oncology Group, and NCI. Dr. Charles Mullighan of St. Jude presented the findings on behalf of the TARGET team at the American Association for Cancer Research annual meeting last month in Denver.
Dr. Mullighan pointed out that JAK genes were mutated in children with ALL who did not also have Down syndrome. Several recent reports described mutations in the JAK2 gene among children who had both ALL and Down syndrome.
"The discovery of activating JAK mutations in a subset of ALL patients is a very important observation with obvious clinical implications," said Dr. Malcolm Smith of NCI's Cancer Therapy Evaluation Program and an NCI leader of the TARGET Initiative. The project is systematically sequencing more than 120 genes suspected of playing a role in ALL.
The incorporation of JAK inhibitors into treatment programs for patients with JAK-mutated ALL is a highly promising line of clinical research that needs to be aggressively pursued, added senior author Dr. Cheryl Willman of the University of New Mexico. She cited the success of imatinib (Gleevec), another kinase inhibitor, as a model.
The researchers are testing JAK inhibitors in their experimental models and hope eventually to move to patients. Genetic tests could be developed to screen patients for changes to the IKAROS and JAK genes, and the results could guide treatment as well as identify patients at risk of relapse, noted Dr. Mullighan.
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