Bercovich Dani, Ganmore Ithamar, Scott Linda M, Wainreb Gilad, Birger Yehudit, Elimelech Arava, Shochat Chen, Cazzaniga Giovanni, Biondi Andrea, Basso Giuseppe, Cario Gunnar, Schrappe Martin, Stanulla Martin, Strehl Sabine, Haas Oskar A, Mann Georg, Binder Vera, Borkhardt Arndt, Kempski Helena, Trka Jan, Bielorei Bella, Avigad Smadar, Stark Batia, Smith Owen, Dastugue Nicole, Bourquin Jean-Pierre, Tal Nir Ben, Green Anthony R, Izraeli Shai
Human Molecular Genetics and Pharmacogenetics Laboratory, Migal-Galilee Biotechnology Centre, Kiryat Shmona, and Tel-Hai Academic College, Israel.
Lancet. 2008 Oct 25;372(9648):1484-92. doi: 10.1016/S0140-6736(08)61341-0. Epub 2008 Sep 19.
Children with Down's syndrome have a greatly increased risk of acute megakaryoblastic and acute lymphoblastic leukaemias. Acute megakaryoblastic leukaemia in Down's syndrome is characterised by a somatic mutation in GATA1. Constitutive activation of the JAK/STAT (Janus kinase and signal transducer and activator of transcription) pathway occurs in several haematopoietic malignant diseases. We tested the hypothesis that mutations in JAK2 might be a common molecular event in acute lymphoblastic leukaemia associated with Down's syndrome.
JAK2 DNA mutational analysis was done on diagnostic bone marrow samples obtained from 88 patients with Down's syndrome-associated acute lymphoblastic leukaemia; and 216 patients with sporadic acute lymphoblastic leukaemia, Down's syndrome-associated acute megakaryoblastic leukaemia, and essential thrombocythaemia. Functional consequences of identified mutations were studied in mouse haematopoietic progenitor cells.
Somatically acquired JAK2 mutations were identified in 16 (18%) patients with Down's syndrome-associated acute lymphoblastic leukaemia. The only patient with non-Down's syndrome-associated leukaemia but with a JAK2 mutation had an isochromosome 21q. Children with a JAK2 mutation were younger (mean [SE] age 4.5 years [0.86] vs 8.6 years [0.59], p<0.0001) at diagnosis. Five mutant alleles were identified, each affecting a highly conserved arginine residue (R683). These mutations immortalised primary mouse haematopoietic progenitor cells in vitro, and caused constitutive Jak/Stat activation and cytokine-independent growth of BaF3 cells, which was sensitive to pharmacological inhibition with JAK inhibitor I. In modelling studies of the JAK2 pseudokinase domain, R683 was situated in an exposed conserved region separated from the one implicated in myeloproliferative disorders.
A specific genotype-phenotype association exists between the type of somatic mutation within the JAK2 pseudokinase domain and the development of B-lymphoid or myeloid neoplasms. Somatically acquired R683 JAK2 mutations define a distinct acute lymphoblastic leukaemia subgroup that is uniquely associated with trisomy 21. JAK2 inhibitors could be useful for treatment of this leukaemia.
Israel Trade Ministry, Israel Science Ministry, Jewish National Fund UK, Sam Waxman Cancer Research Foundation, Israel Science Foundation, Israel Cancer Association, Curtis Katz, Constantiner Institute for Molecular Genetics, German-Israel Foundation, and European Commission FP6 Integrated Project EUROHEAR.
唐氏综合征患儿患急性巨核细胞白血病和急性淋巴细胞白血病的风险大幅增加。唐氏综合征相关的急性巨核细胞白血病的特征是GATA1基因发生体细胞突变。JAK/STAT（Janus激酶和信号转导及转录激活因子）通路的组成性激活发生在多种血液系统恶性疾病中。我们检验了JAK2基因的突变可能是唐氏综合征相关急性淋巴细胞白血病常见分子事件的假说。
对88例唐氏综合征相关急性淋巴细胞白血病患者、216例散发性急性淋巴细胞白血病患者、唐氏综合征相关急性巨核细胞白血病患者及原发性血小板增多症患者的诊断性骨髓样本进行JAK2基因DNA突变分析。在小鼠造血祖细胞中研究已鉴定突变的功能后果。
在16例（18%）唐氏综合征相关急性淋巴细胞白血病患者中鉴定出体细胞获得性JAK2突变。唯一1例非唐氏综合征相关白血病但有JAK2突变的患者存在21号染色体等臂染色体。诊断时，有JAK2突变的患儿年龄更小（平均[标准误]年龄4.5岁[0.86]对8.6岁[0.59]，p<0.0001）。鉴定出5个突变等位基因，每个都影响一个高度保守的精氨酸残基（R683）。这些突变在体外使原代小鼠造血祖细胞永生化，并导致BaF3细胞发生组成性Jak/Stat激活和细胞因子非依赖性生长，该细胞对JAK抑制剂I的药理学抑制敏感。在JAK2假激酶结构域的建模研究中，R683位于一个与骨髓增殖性疾病相关区域分离的暴露保守区域。
JAK2假激酶结构域内的体细胞突变类型与B淋巴细胞或髓系肿瘤的发生之间存在特定的基因型-表型关联。体细胞获得性R683 JAK2突变定义了一个独特的急性淋巴细胞白血病亚组，该亚组与21三体综合征独特相关。JAK2抑制剂可能对治疗这种白血病有用。
以色列贸易部、以色列科学部、英国犹太民族基金会、萨姆·韦克斯曼癌症研究基金会、以色列科学基金会、以色列癌症协会、柯蒂斯·卡茨、康斯坦丁纳分子遗传学研究所、德以基金会和欧盟委员会FP6综合项目EUROHEAR。
