Activating alleles of JAK3 in acute megakaryoblastic leukemia
Activating alleles of JAK3 in acute megakaryoblastic leukemia
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DOI：
10.1016/j.ccr.2006.06.002
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发表时间：
2006-07-01
期刊：
影响因子：
50.3
通讯作者：
Druker, Brian J.
中科院分区：
文献类型：
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作者：
Walters, Denise K.;Mercher, Thomas;Druker, Brian J.
酪氨酸激酶在多种恶性肿瘤中异常激活，包括急性髓系白血病 (AML)。为了识别 AML 中激活的酪氨酸激酶，我们开发了一种筛选策略，可以使用质谱快速识别酪氨酸磷酸化蛋白。这使得在急性巨核细胞白血病 (AMKL) 细胞系 CMK 的 JAK3 假激酶结构域中鉴定出激活突变 (A572V)。随后的分析在 AMKL 患者中发现了另外两个 JAK3 等位基因：V722I 和 P132T。 JAK3(A572V)、JAK3(P132T) 和 JAK3P132T 均将 Ba/F3 细胞转化为因子独立生长，并且 JAK3 A572V 在小鼠模型中赋予巨核细胞白血病的特征。这些发现说明了功能获得性 JAK3 突变在白血病发生中的生物学重要性，并证明了蛋白质组学方法在识别临床相关突变方面的实用性。
Tyrosine kinases are aberrantly activated in numerous malignancies, including acute myeloid leukemia (AML). To identify tyrosine kinases activated in AML, we developed a screening strategy that rapidly identifies tyrosine-phosphorylated proteins using mass spectrometry. This allowed the identification of an activating mutation (A572V) in the JAK3 pseudokinase domain in the acute megakaryoblastic leukemia (AMKL) cell line CMK. Subsequent analysis identified two additional JAK3 alleles, V722I and P132T, in AMKL patients. JAK3(A572V), JAK3(P132T), and JAK3P132T each transform Ba/F3 cells to factor-independent growth, and JAK3 A572V confers features of megakaryoblastic leukemia in a murine model. These findings illustrate the biological importance of gain-of-function JAK3 mutations in leukemogenesis and demonstrate the utility of proteomic approaches to identifying clinically relevant mutations.