Identification of a homozygous JAK3 V674A mutation caused by acquired uniparental disomy in a relapsed early T-cell precursor ALL patient.
Identification of a homozygous JAK3 V674A mutation caused by acquired uniparental disomy in a relapsed early T-cell precursor ALL patient.
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鉴定复发性早期 T 细胞前体 ALL 患者中由获得性单亲二体性引起的纯合 JAK3 V674A 突变。
DOI：
10.1007/s12185-014-1711-y
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发表时间：
2015
期刊：
影响因子：
--
通讯作者：
Hosoi H.
中科院分区：
文献类型：
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作者：
Kawashima-Goto S;Imamura T;Seki M;Kato M;Yoshida K;Sugimoto A;Kaneda D;Fujiki A;Miyachi M;Nakatani T;Osone S;Ishida H;Taki T;Takita J;Shiraishi Y;Chiba K;Tanaka H;Miyano S;Ogawa S;Hosoi H.
研究急性淋巴细胞白血病（ALL）复发相关的遗传改变可能有助于确定特定治疗的药物靶点。早期T细胞前体ALL（ETP ALL）是T细胞ALL的一种亚型，预后不良。虽然ETP-ALL的遗传格局已经确定，但与ETP-ALL复发相关的遗传改变尚未得到充分研究。在这里，我们报告了第一个复发的儿科ETP-ALL患者表现出纯合子JAK 3激活突变，V674 A，由获得性单亲二体性（UPD）引起。单核苷酸多态性阵列分析显示，获得性UPD（aUPD）在19p13.3-p12位点仅在白血病细胞复发。在配对的白血病样本中，对位于19 p13.1且在ETP-ALL中频繁突变的JAK 3基因进行桑格测序，以确定仅在复发的白血病细胞中的纯合JAK 3 V674 A突变。相反，白血病细胞在初次诊断时具有半合子JAK 3 V674 A突变。此外，全外显子组测序仅在复发样本中发现了18个基因的突变，尽管这些突变在T-ALL中均未复发。这些结果表明，aUPD在19p13.1是部分与复发的患者。JAK 3的药理学抑制在这种情况下可能是治疗性的。
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 theJAK3gene, 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.