Inhibition of FLT3 in MLL: Validation of a therapeutic target identified by gene expression based classification
Inhibition of FLT3 in MLL: Validation of a therapeutic target identified by gene expression based classification
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DOI：
10.1016/s1535-6108(03)00003-5
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发表时间：
2003-02-01
期刊：
影响因子：
50.3
通讯作者：
Korsmeyer, SJ
中科院分区：
文献类型：
--
作者：
Armstrong, SA;Kung, AL;Korsmeyer, SJ
我们最近发现，MLL重排的急性淋巴细胞白血病（MLL）具有独特的基因表达谱，包括受体酪氨酸激酶FLT 3的高水平表达。我们假设FLT 3可能是MLL的治疗靶点，并发现30个MLL中有5个在FLT 3的激活环中含有突变，导致组成性激活。三个是新描述的1836缺失，其他是D835突变。最近描述的FLT 3抑制剂PKC 412被证明对Ba/F3细胞具有细胞毒性，依赖于含有任一突变的活化FLT 3。PKC 412对MLL易位白血病细胞和FLT 3也有不同的细胞毒性，FLT 3通过野生型受体或突变的过表达而激活。最后，我们建立了小鼠MLL模型，并使用生物发光成像来确定PKC 412在体内对MLL具有活性。
We recently found that MLL-rearranged acute lymphoblastic leukemias (MLL) have a unique gene expression profile including high level expression of the receptor tyrosine kinase FLT3. We hypothesized that FLT3 might be a therapeutic target in MLL and found that 5 of 30 MLLs contain mutations in the activation loop of FLT3 that result in constitutive activation. Three are a newly described deletion of 1836 and the others are D835 mutations. The recently described FLT3 inhibitor PKC412 proved cytotoxic to Ba/F3 cells dependent upon activated FLT3 containing either mutation. PKC412 is also differentially cytotoxic to leukemia cells with MLL translocations and FLT3 that is activated by either overexpression of the wild-type receptor or mutation. Finally, we developed a mouse model of MLL and used bioluminescent imaging to determine that PKC412 is active against MLL in vivo.