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JAK mutations associated with poor outcome in children with ALL
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AACR 100th Annual Meeting
Data from the first Therapeutically Applicable Research to Generate Effective Treatments (TARGET) initiative demonstrate that JAK mutations occur in some children with B-progenitor acute lymphoblastic leukemia. The mutations were associated with IKZF1 and CDKN2A/B deletion and poor outcome.
“These mutations are transforming; they’re switched off by JAK inhibitors and so this would suggest that JAK inhibition should be pursued in clinical studies of this subtype of leukemia,” Charles G. Mullighan, MBBS (Hons), MSc, MD, department of pathology, St. Jude Children’s Research Hospital in Tennessee, said during his presentation.
Using data from a Children’s Oncology Group study, researchers studied 221 children with B-progenitor ALL at high risk for relapse with no known high-risk genetic alterations. The researchers conducted genomic resequencing of the Janus kinase genes JAK1, JAK2, JAK3 and TYK2 in 187 cases of ALL.
The researchers identified 20 somatic, heterozygous, non-silent coding mutations in 10.7% of patients, all of whom lacked previously identified recurring translocations. JAK2 was mutated in 16 patients most commonly at or near R683 in the JAK2 pseudokinase domain.
Novel mutations were identified in the JAK2 kinase domain, JAK1 pseudokinase domain and JAK3. The mutations involved highly conserved residues in the kinase or pseudokinase JAK domains except for JAK3 S789P. Though previous studies suggested JAK2 mutations in ALL are only observed in patients with Down syndrome, the researchers found that only two of the mutations that involved patients with ALL and Down syndrome (n=9 sequenced).
Among patients with JAK and IKZF1 alterations, the four-year incidence of relapse was 71% compared with 23% for patients with neither alteration (P=.0004). According to the researchers, the gene expression profile of JAK-mutated ALL was similar to that of BCR-ABL1 ALL.
“Future studies we have planned and are ongoing continue to look through the kinase genes to find other kinase alterations in these cases to try to move these findings forward to the clinic and look at additional cohorts of ALL cases,” Mullighan said. – by Stacey L. Adams
One important aspect of his presentation was indicating that they're going to look at these mutations in additional samples. Confirming these results in additional populations is needed to validate the findings.
– John Witte, PhD
Professor in The Institute of Human Genetics at the University of California at San Francisco
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