Biological characteristics and prognosis of adult acute myeloid leukemia with internal tandem duplications in the Flt3 gene
Biological characteristics and prognosis of adult acute myeloid leukemia with internal tandem duplications in the Flt3 gene
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DOI：
10.1038/sj.leu.2401731
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发表时间：
2000-04-01
期刊：
影响因子：
11.4
通讯作者：
Ploemacher, RE
中科院分区：
文献类型：
--
作者：
Rombouts, WJC;Blokland, I;Ploemacher, RE
FIt 3基因的内部串联重复（FIt 3/ITD）存在于约18%的所有AML病例中，因此是AML中最常见的体细胞基因突变之一。关于FIt 3/ITDs在白血病发生中的作用或其临床相关性知之甚少。在这项研究中，我们比较了18个样本与FIT 3/ITDs和63个AML样本没有这些突变的临床预后，细胞因子反应性，祖细胞含量和再增殖的NOD/SCID小鼠。我们发现，突变患者的CR率降低（P=0.03），复发率增加（P=0.01），表明FIt 3/ITDs的预后重要性。这一点也被以下发现所强调：在60岁以下的患者中，以及在老年患者中，突变患者的无事件生存率更不利（分别为P=0.003和P=0.03）。在诊断时，FIT 3/ITD和非突变AML骨髓样本的祖细胞/干细胞频率没有差异。鹅卵石区域形成细胞（CAFC）的子集显示了类似的频率分布在突变和非突变样本。在7天的液体培养中，FIt 3/ITD样品显示出响应于多种骨髓生长因子的生长减少。相反，FIT 3/ITD样品显示出更高的能力，植入NOD/SCID骨髓与白血病细胞。总之，这些数据表明，FIt 3/ITD代表了患者预后的重要诊断标志物，并且这些突变的存在与体内和体外祖细胞增殖能力的改变相关。
internal tandem duplications of the FIt3 gene (FIt3/ITDs) are present in about 18% of all AML cases and are therefore one of the most frequent somatic gene mutations in AML. Little is known about the role of FIt3/ITDs in leukemogenesis or their clinical relevance. In this study we compared 18 samples with FIt3/ITDs and 63 AML samples without these mutations with respect to clinical prognosis, cytokine responsiveness, progenitor cell content and repopulation in the NOD/SCID mouse. We found that in patients with a mutation CR rates are reduced (P=0.03) and relapse rates are increased (P=0.01), indicating the prognostic importance of FIt3/ITDs. This is also emphasized by the finding that in patients under the age of 60 years, as well as in older patients the event-free survival was more unfavorable for the mutant patients (P=0.003 and P=0.03, respectively). At diagnosis FIt3/ITD and non-mutant AML bone marrow samples did not differ in their progenitor/stem cell frequencies. Cobblestone area forming cell (CAFC) subsets showed a similar frequency distribution in mutant and nonmutant samples. In 7-day liquid cultures, FIt3/ITD samples showed a reduced growth in response to a variety of myeloid growth factors. In contrast, FIt3/ITD samples displayed a higher ability to engraft the NOD/SCID bone marrow with leukemic cells. Together these data show that the FIt3/ITD represents an important diagnostic marker for patient prognosis, and that the presence of these mutations is associated with altered proliferative ability of progenitors in vivo and in vitro.