Internal tandem duplication of FLT3 associated with leukocytosis in acute promyelocytic leukemia
Internal tandem duplication of FLT3 associated with leukocytosis in acute promyelocytic leukemia
复制标题
DOI：
10.1038/sj.leu.2400756
复制
发表时间：
1997-09-01
期刊：
影响因子：
11.4
通讯作者：
Ohno, R
中科院分区：
文献类型：
--
作者：
Kiyoi, H;Naoe, T;Ohno, R
FLT 3是在白血病细胞以及造血干细胞中表达的受体酪氨酸激酶的成员。最近，在急性髓性白血病中发现了FLT 3基因的体细胞改变，作为内部串联重复（FLT 3/ITD），其引起FLT 3的跨膜（JM）结构域的延长。本研究对FLT 3/ITD进行了表征，并探讨了其在急性早幼粒细胞白血病（APL）中的临床意义。在一项多机构研究中，对74例新诊断的APL患者进行了FLT 3/ITD研究。通过聚合酶链反应（PCR）扩增FLT 3基因的基因组和信息序列，并对延长的PCR产物进行测序。15例（20.3%）患者有FLT 3/ITD，所有这些都在框架内转录。重复片段的位置（6至30个氨基酸）因患者而异。然而，它们总是含有Y 591或Y 599，但酪氨酸激酶结构域没有受到显着影响。这一发现暗示FLT 3的信号转导通过复制被放大。临床上，FLT 3/ITD的存在与外周血白色细胞计数以及外周血白血病细胞计数高（P < 0.0001）、LDH水平高（P = 0.04）和纤维蛋白原浓度低（P = 0.04）相关。这些数据表明FLT 3/ITD在APL的进展中起重要作用。
FLT3 is a member of receptor tyrosine kinases expressed in leukemia cells, as well as in hematopoietic stem cells. Recently, a somatic alteration of the FLT3 gene was found in acute myeloid leukemia, as an internal tandem duplication (FLT3/ITD) which caused elongation of the juxtamembrane (JM) domain of FLT3. Here we characterized the FLT3/ITD and investigated its clinical significance in acute promyelocytic leukemia (APL). Seventy-four newly diagnosed patients with APL, who were treated with the same protocol in a multi-institutional study, were studied for the FLT3/ITD. Genomic and message sequences of the FLT3 gene were amplified by means of polymerase chain reaction (PCR), and elongated PCR products were sequenced. Fifteen patients (20.3%) had FLT3/ITD, all of which were transcribed in frame. Location of the duplicated fragments (six to 30 amino acids) varied from patient to patient. However, they always contained either Y591 or Y599, but the tyrosine kinase domain was not significantly affected. This finding implied that signal transduction of FLT3 is amplified by the duplication. Clinically, the presence of FLT3/ITD was related to high peripheral white blood cell counts as well as peripheral leukemia cell counts (P < 0.0001), high LDH level (P = 0.04), and low fibrinogen concentration (P = 0.04). These data suggest that FLT3/ITD plays a significant role in progression of APL.