FLT3 is fused to ETV6 in a myeloproliferative disorder with hypereosinophilia and a t(12;13) (p13;q12) translocation
FLT3 is fused to ETV6 in a myeloproliferative disorder with hypereosinophilia and a t(12;13) (p13;q12) translocation
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DOI：
10.1038/sj.leu.2404266
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发表时间：
2006-08-01
期刊：
影响因子：
11.4
通讯作者：
Sato, Y.
中科院分区：
文献类型：
--
作者：
Vu, Ha;Xinh, Pt;Sato, Y.
FMS样酪氨酸激酶3(FMS-like tyroine kinase3，Flt3)基因属于受体酪氨酸激酶(TK)亚类III家族，在正常造血过程中起重要作用，是恶性血液病中最常见的突变基因之一，也是有吸引力的定向抑制靶点。该基因的激活突变，包括膜旁(JM)区域的内部串联复制和TK区域的点突变，在大约三分之一的急性髓系白血病患者和一小部分急性淋巴细胞白血病患者中被发现。我们在这里报道，Flt3可能通过产生与ETS变异基因6(ETV6)基因的融合基因而参与骨髓增殖性疾病和t(12；13)(p13；q12)易位患者的白血病发生。ETV6已被报道与多种伴侣基因融合，包括TK和转录因子。逆转录-聚合酶链式反应检测到ETV6/Flt3和正反转录的flt3/ETV6转录本。然而，在蛋白质水平上，只表达了ETV6/Flt3产物。其中一个保留了ETV6的螺旋-环-螺旋(HLH)低聚域和Flt3的JM和TK结构域。白血病细胞的Flt3受体可能通过ETV6的HLH域的二聚化而被异常激活，从而干扰造血细胞的增殖和分化。
The FMS-like tyrosine kinase 3 (FLT3) gene, belonging to the receptor tyrosine kinase (TK) subclass III family, plays an important role in normal hematopoiesis and is one of the most frequently mutated genes in hematologic malignancies as well as an attractive target for directed inhibition. Activating mutations of this gene, including internal tandem duplication in the juxtamembrane (JM) domain and point mutations in the TK domain, are found in approximately one-third of patients with acute myeloid leukemia and in a smaller subset of patients with acute lymphoblastic leukemia. We report here that FLT3 may contribute to leukemogenesis in a patient with myeloproliferative disorder and a t(12;13)(p13;q12) translocation through generating a fusion gene with the ETS variant gene 6 (ETV6) gene. ETV6 has been reported to fuse to various partner genes, including TK and transcription factors. Both ETV6/FLT3 and reciprocal FLT3/ETV6 transcripts were detected in the patient mRNA by reverse transcriptase-polymerase chain reaction. At the protein level, however, only ETV6/FLT3 products were expressed. Among them, one retains the helix-loop-helix (HLH) oligomerization domain of ETV6 and the JM as well as TK domain of FLT3. FLT3 receptor in leukemic cells might be inappropriately activated through dimerization by HLH domain of ETV6, which consequently interfered with proliferation and differentiation of hematopoietic cells.