急性早幼粒细胞白血病中与白细胞增多相关的FLT3内部串联重复。厚生省白血病研究组。

Internal tandem duplication of FLT3 associated with leukocytosis in acute promyelocytic leukemia. Leukemia Study Group of the Ministry of Health and Welfare (Kohseisho).

作者信息

Kiyoi H, Naoe T, Yokota S, Nakao M, Minami S, Kuriyama K, Takeshita A, Saito K, Hasegawa S, Shimodaira S, Tamura J, Shimazaki C, Matsue K, Kobayashi H, Arima N, Suzuki R, Morishita H, Saito H, Ueda R, Ohno R

机构信息

Nagoya University School of Medicine, Japan.

出版信息

Leukemia. 1997 Sep;11(9):1447-52. doi: 10.1038/sj.leu.2400756.

DOI:10.1038/sj.leu.2400756

PMID:9305596

Abstract

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.

摘要

FLT3是一种受体酪氨酸激酶，在白血病细胞以及造血干细胞中均有表达。最近，在急性髓系白血病中发现了FLT3基因的体细胞改变，即内部串联重复（FLT3/ITD），它导致FLT3近膜（JM）结构域延长。在此，我们对FLT3/ITD进行了表征，并研究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例采用相同方案治疗的新诊断APL患者进行了FLT3/ITD检测。通过聚合酶链反应（PCR）扩增FLT3基因的基因组和信使序列，并对延长的PCR产物进行测序。15例患者（20.3%）存在FLT3/ITD，所有这些均为框内转录。重复片段的位置（6至30个氨基酸）因患者而异。然而，它们总是包含Y591或Y599，但酪氨酸激酶结构域未受到显著影响。这一发现表明FLT3的信号转导通过重复而增强。在临床上，FLT3/ITD的存在与外周血白细胞计数升高以及外周白血病细胞计数升高（P < 0.0001）、乳酸脱氢酶水平升高（P = 0.04）和纤维蛋白原浓度降低（P = 0.04）相关。这些数据表明FLT3/ITD在APL进展中起重要作用。