Identification of a homozygous JAK3 V674A mutation caused by acquired uniparental disomy in a relapsed early T-cell precursor ALL patient

Investigation of genetic alterations associated with relapse in acute lymphoblastic leukemia (ALL) may help to identify druggable targets for specific therapies. Early T-cell precursor ALL (ETP-ALL) is a subtype of T-ALL with poor prognosis. Although the genetic landscape of ETP-ALL has been determined, genetic alterations related to the relapse of ETP-ALL have not been fully investigated. Here, we report the first patient with relapsed pediatric ETP-ALL to exhibit a homozygous JAK3 activating mutation, V674A, caused by acquired uniparental disomy (UPD). Single nucleotide polymorphism array analysis revealed acquired UPD (aUPD) at the 19p13.3-p12 locus only in leukemic cells at relapse. Sanger sequence of the JAK3 gene, which was located at 19p13.1 and frequently mutated in ETP-ALL, was performed in paired leukemic samples to determine homozygous JAK3 V674A mutation only in relapsed leukemic cells. In contrast, leukemic cells at initial diagnosis harbored hemizygous JAK3 V674A mutation. Further, whole-exome sequencing revealed mutations in 18 genes only in relapsed samples, although none of these was recurrent in T-ALL. These findings suggest that aUPD at 19p13.1 is partly associated with relapse in this patient. Pharmacological inhibition of JAK3 may be therapeutic in such cases.