title: Identification of a homozygous JAK3 V674A mutation caused by acquired uniparental disomy in a relapsed early T-cell precursor ALL patient.
abstract: 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.
authors.affiliation: Department of Pediatrics, Kyoto Prefectural University of Medicine, Graduate School of Medical Science, Kajii-cho Hirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan.
authors.forename: Sachiko
authors.initials: S
authors.lastname: Kawashima-Goto
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Imamura
authors.forename: Masafumi
authors.initials: M
authors.lastname: Seki
authors.forename: Motohiro
authors.initials: M
authors.lastname: Kato
authors.forename: Kenichi
authors.initials: K
authors.lastname: Yoshida
authors.forename: Atsuya
authors.initials: A
authors.lastname: Sugimoto
authors.forename: Daisuke
authors.initials: D
authors.lastname: Kaneda
authors.forename: Atsushi
authors.initials: A
authors.lastname: Fujiki
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Miyachi
authors.forename: Takuya
authors.initials: T
authors.lastname: Nakatani
authors.forename: Shinya
authors.initials: S
authors.lastname: Osone
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Ishida
authors.forename: Tomohiko
authors.initials: T
authors.lastname: Taki
authors.forename: Junko
authors.initials: J
authors.lastname: Takita
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Shiraishi
authors.forename: Kenichi
authors.initials: K
authors.lastname: Chiba
authors.forename: Hiroko
authors.initials: H
authors.lastname: Tanaka
authors.forename: Satoru
authors.initials: S
authors.lastname: Miyano
authors.forename: Seishi
authors.initials: S
authors.lastname: Ogawa
authors.forename: Hajime
authors.initials: H
authors.lastname: Hosoi
mesh_terms: D000293:Adolescent; D001483:Base Sequence; D006720:Homozygote; D006801:Humans; D053616:Janus Kinase 3 / Q000235:genetics*; D008297:Male; D017354:Point Mutation; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics*; D024182:Uniparental Disomy / Q000235:genetics*
chemical_list: D053616:Janus Kinase 3