Fröhling Stefan, Scholl Claudia, Levine Ross L, Loriaux Marc, Boggon Titus J, Bernard Olivier A, Berger Roland, Döhner Hartmut, Döhner Konstanze, Ebert Benjamin L, Teckie Sewit, Golub Todd R, Jiang Jingrui, Schittenhelm Marcus M, Lee Benjamin H, Griffin James D, Stone Richard M, Heinrich Michael C, Deininger Michael W, Druker Brian J, Gilliland D Gary
Division of Hematology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Cancer Cell. 2007 Dec;12(6):501-13. doi: 10.1016/j.ccr.2007.11.005.
Mutations in the juxtamembrane and kinase domains of FLT3 are common in AML, but it is not known whether alterations outside these regions contribute to leukemogenesis. We used a high-throughput platform to interrogate the entire FLT3 coding sequence in AML patients without known FLT3 mutations and experimentally tested the consequences of each candidate leukemogenic allele. This approach identified gain-of-function mutations that activated downstream signaling and conferred sensitivity to FLT3 inhibition and alleles that were not associated with kinase activation, including mutations in the catalytic domain. These findings support the concept that acquired mutations in cancer may not contribute to malignant transformation and underscore the importance of functional studies to distinguish "driver" mutations underlying tumorigenesis from biologically neutral "passenger" alterations.
FLT3近膜区和激酶结构域的突变在急性髓系白血病（AML）中很常见，但尚不清楚这些区域以外的改变是否有助于白血病的发生。我们使用了一个高通量平台来检测没有已知FLT3突变的AML患者的整个FLT3编码序列，并通过实验测试了每个候选致白血病等位基因的后果。这种方法鉴定出了激活下游信号传导并赋予对FLT3抑制敏感性的功能获得性突变，以及与激酶激活无关的等位基因，包括催化结构域中的突变。这些发现支持了癌症中获得性突变可能无助于恶性转化的概念，并强调了功能研究对于区分肿瘤发生背后的“驱动”突变与生物学上中性的“乘客”改变的重要性。
