Children with Down Syndrome (DS) have an increased risk of developing leukemia, including both acute myeloid (ML DS), as well as acute lymphoblastic leukemia (DSALL). Recently, Izraeli et al. reported on an activating mutation (R683) localized in exon 16 of the Janus Kinase 2 (JAK2) gene, in 18% of DS-ALL (n=16) patients collected from 9 European study groups (ASH 2007). Screening of other leukemia subsets showed that this mutation was exclusive for DS-ALL patients. This JAK2 mutation differs from the V617F exon 14 mutation found in myeloproliferative diseases. JAK2 is located on chromosome 9p24, and belongs to a family of intracellular non-receptor protein tyrosine kinases that transduce cytokine-mediated signals via the JAK-STAT pathway. It plays an important role in regulating the processes of cell proliferation, differentiation and apoptosis in response to cytokines and growth factors. Between 1991 and 2007, 45 children with DS ALL were treated in the Netherlands, according to the DCOG protocols ALL 7–10. Of 36 children samples were available in the DCOG cell bank, on which we performed JAK2 mutation screening of the pseudokinase and kinase domains of JAK2 by direct sequencing. All 36 patients were classified as BCP-ALL. Mutations in JAK2 exon 16 were identified in 6 (16.6%) DS-ALL patients. In five patients a point mutation resulted in substitution of Arginine at position 683, the same as was described by Izraeli et al. In one patient an insertion was found. JAK2 mutated patients did not differ in age at diagnosis (3.3 vs. 5.1 years, p=0.08) or in sex (p= 0.8) compared to non-mutated DSALL patients. The diagnostic WBC for DS-ALL patients with a JAK2 exon 16 mutation was lower than for non-mutated patients (3.6×109/L vs. 12.1×109/L; p=0.04). Ploidy status based on karyotyping was known in 29/36 patients. None of the JAK2 mutated samples was hyperdiploid (>52 chromosomes) vs. one in the non-mutated samples (p=0.89). TEL/AML rearrangements were screened in 23/36 samples, and 3/23 (13%) samples showed a TEL-AML rearrangement. None of the JAK2 mutated samples was TEL-AML rearranged (p= 0.76). One JAK2 mutated patient had a normal karyotype, the other JAK2 mutated patients had random cytogenetic abnormalities. We next analyzed the prognostic significance of JAK2 mutated DS-ALL children versus the other patients. The median follow up time for all patients was 3.1 years (range 0.1–15.1 years). Interestingly, none of the JAK2 mutated patients relapsed, versus 4/30 wild type JAK2 patients. The differences between pOS (100% vs. 83.3% p=0.41), pEFS (100% vs. 80%, p=0.38) and pDFS (100% vs. 82.8%, p=0.44) were not statistically significant, probably due to small numbers. Since DS-ALL children are more sensitive to the side effects of chemotherapy, and have relatively high toxic mortality rates, reduction of therapy intensity might be an option for DS-ALL children with a JAK2 exon 16 mutation, if our results could be confirmed in larger series. The development of specific JAK2 inhibitors may allow further reduction of chemotherapy.

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