文章：

FLT3调节抗原作为白血病反应性细胞毒性T淋巴细胞的靶标

FLT3-regulated antigens as targets for leukemia-reactive cytotoxic T lymphocytes

原文发布日期：2011-03-18

DOI: 10.1038/bcj.2011.12

类型: Original Article

开放获取: 是

英文摘要：

The FMS-like tyrosine kinase 3 (FLT3) is highly expressed in acute myeloid leukemia (AML). Internal tandem duplications (ITD) of the juxtamembrane domain lead to the constitutive activation of the FLT3 kinase inducing the activation of multiple genes, which may result in the expression of leukemia-associated antigens (LAAs). We analyzed the regulation of LAA in FLT3-wild-type (WT)- and FLT3-ITD+ myeloid cells to identify potential targets for antigen-specific immunotherapy for AML patients. Antigens, such as PR-3, RHAMM, Survivin, WT-1 and PRAME, were upregulated by constitutively active FLT3-ITD as well as FLT3-WT activated by FLT3 ligand (FL). Cytotoxic T-cell (CTL) clones against PR-3, RHAMM, Survivin and an AML-directed CTL clone recognized AML cell lines and primary AML blasts expressing FLT3-ITD, as well as FLT3-WT+ myeloid dendritic cells in the presence of FL. Downregulation of FLT3 led to the abolishment of CTL recognition. Comparing our findings concerning LAA upregulation by the FLT3 kinase with those already made for the Bcr-Abl kinase, we found analogies in the LAA expression pattern. Antigens upregulated by both FLT3 and Bcr-Abl may be promising targets for the development of immunotherapeutical approaches against myeloid leukemia of different origin.

摘要翻译： 

FMS样酪氨酸激酶3（FLT3）在急性髓系白血病（AML）中高表达。近膜结构域的内部串联重复（ITD）导致FLT3激酶构成性激活，进而诱导多个基因的活化，这可能引发白血病相关抗原（LAAs）的表达。我们分析了FLT3野生型（WT）和FLT3-ITD+髓系细胞中LAA的调控机制，以确定AML患者抗原特异性免疫治疗的潜在靶点。组成性激活的FLT3-ITD以及经FLT3配体（FL）激活的FLT3-WT均能上调PR-3、RHAMM、Survivin、WT-1和PRAME等抗原的表达。针对PR-3、RHAMM、Survivin的细胞毒性T细胞（CTL）克隆及一个AML定向CTL克隆，能够识别表达FLT3-ITD的AML细胞系和原代AML原始细胞，以及在FL存在下的FLT3-WT+髓系树突状细胞。下调FLT3表达则消除了CTL的识别能力。通过比较FLT3激酶与已研究的Bcr-Abl激酶对LAA的上调作用，我们发现两者在LAA表达模式上存在相似性。受FLT3和Bcr-Abl共同上调的抗原可能成为针对不同来源髓系白血病开发免疫治疗方法的有前景靶点。

原文链接：

FLT3-regulated antigens as targets for leukemia-reactive cytotoxic T lymphocytes