Abstract

Approximately three-quarters of pediatric acute lymphoblastic leukemia (ALL) cases harbor recurrent, prognostically significant chromosomal abnormalities which affect assignment of risk group and therapeutic regimen, but these abnormalities occur far less often in children with Down syndrome (DS) and ALL. Recently, novel somatic activating mutations in Janus kinase 2 (JAK2) were reported to occur uniquely in DS ALL, affecting 18% of patients (Bercovich et al, in press). Here we report the identification and clinical correlates of JAK2 mutations in an independent cohort of cases. We sequenced JAK2 exon 16 and identified mutations in 10 of 53 DS ALL cases (18.9%). All were heterozygous point mutations affecting arginine 683 (Table 1). No JAK2 mutations were identified in the 25 available paired germline DS samples, including five germline samples associated with JAK2 mutated ALL cases, indicating that mutations were somatic in these cases. Eight of the JAK2 mutations (80%) occurred in males (p<0.03), whereas the full cohort contained 24 males (45%). No significant correlation was observed between JAK2 mutation status and age, initial white blood count (WBC), or 5-year event-free survival or overall survival. Our results confirm the 18% prevalence of JAK2 mutations at arginine 683 in DS ALL, but differ from the prior report in finding a male predominance of JAK2 mutations, and no association with age or initial WBC, differences which may be attributable to sample size. These results confirm that activation of the JAK-STAT pathway via a specific JAK2 mutation occurs in approximately one-fifth of cases of DS ALL.

Sequence Amino acid Cases (n) 
AGA (wild-type) Arginine 43 
GGA Glycine 
AGT Serine 
AGC Serine 
ACA Threonine 
Sequence Amino acid Cases (n) 
AGA (wild-type) Arginine 43 
GGA Glycine 
AGT Serine 
AGC Serine 
ACA Threonine 

Table 1.JAK2mutation status in pediatric DS ALL

Disclosures: No relevant conflicts of interest to declare.

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