Kiyoi Hitoshi, Naoe Tomoki
Department of Infectious Diseases, Nagoya University School of Medicine, Japan.
Leuk Lymphoma. 2002 Aug;43(8):1541-7. doi: 10.1080/1042819021000002866.
FLT3, a member of the receptor tyrosine kinase (RTK) class III, is preferentially expressed on the surface of a high proportion of acute myeloid leukemia (AML) and B-lineage acute lymphocytic leukemia (ALL) cells in addition to hematopoietic stem cells, brain, placenta and liver. An interaction of FLT3 and its ligand has been shown to play an important role in the survival, proliferation and differentiation of not only normal hematopoetic cells but also leukemia cells. Mutations of the FLT3 gene was first reported as an internal tandem duplication (ITD) of the juxtamembrane (JM) domain-coding sequence, subsequently as a missense mutation of D835 within a kinase domain. ITD- and D835-mutations are essentially found in AML and their frequencies are approximately 20 and 6% of adults with AML, respectively. Thus, mutation of the FLT3 gene is so far the most frequent genetic alteration reported to be involved in AML. Several large-scale studies in well-documented patients published to date have demonstrated that ITD-mutation is strongly associated with leukocytosis and a poor prognosis. In this review, we summarize the clinical and biological significance of FLT3-mutations and discuss the possibility of targeting FLT3 kinase for the treatment of leukemia.
FMS样酪氨酸激酶3（FLT3）是III类受体酪氨酸激酶（RTK）家族的成员，除了在造血干细胞、脑、胎盘和肝脏中表达外，还在高比例的急性髓性白血病（AML）细胞和B系急性淋巴细胞白血病（ALL）细胞表面优先表达。研究表明，FLT3与其配体的相互作用不仅在正常造血细胞的存活、增殖和分化中，而且在白血病细胞的存活、增殖和分化中都起着重要作用。FLT3基因的突变最初报道为近膜（JM）结构域编码序列的内部串联重复（ITD），随后报道为激酶结构域内D835的错义突变。ITD和D835突变主要见于AML患者，在成年AML患者中的发生率分别约为20%和6%。因此，FLT3基因的突变是迄今为止报道的AML中最常见的基因改变。迄今为止发表的几项针对记录良好患者的大规模研究表明，ITD突变与白细胞增多症和不良预后密切相关。在这篇综述中，我们总结了FLT3突变的临床和生物学意义，并讨论了将FLT3激酶作为白血病治疗靶点的可能性。
