Point mutations of the AML1 gene in patients with leukemia : implications in leukemogenesis, progression, and recurrence

白血病患者 AML1 基因的点突变：对白血病发生、进展和复发的影响

• 批准号: 12670996
• 负责人: ASOU Norio
• 金额: $ 2.18万
• 依托单位: Kumamoto University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2000
• 资助国家: 日本
• 起止时间: 2000 至 2001
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-12670996/
• 关键词: AML1; PEBP2β; acute myeloblastic leukemia; myelodysplastic syndrome; familial platelet disorder; haploinsufficiency; missense mutation; ミスセンス異変; ハプロ接合体異常; ミスセンス変異; AML1; 慢性骨髄性白血病; 急性転化; t(8;21)

A Runt domain transeriptibn factor AML1/RUNX1 is essential for generation and differentiation of difinitive hematopoietic stem cells. AML1 is the most frequent target of chromosomal translocations in acute leukemias. Several chimericproteins such as AML1-MTG8 and TEL-AML1 have transdominant properties for wild-type AML1 and acts as transcriptional repressors. On the other hand, mutations in the Runt domain of the AML1 are identified in both sporadic acute myeloblastic leukemia (AML) without AML1 translocation and familial platelet disorder with predisposition to AML (FPD/AML). In this study, we identified mutations of the AML1 gene in 5 of 25 (20%) patients with AML M0 subtype. We also found mutations of the AML1 gene in 2 pidigrees of FPD/AML. These observations indicate that a decrease in AML1 dosage resulting from chromosomal translocations or mutations contributes to leukemogenesis. Functional analysis of AML1 mutants in the FPD/AML pedigrees showed two types of mutations of the AML1 gene : loss-of-function mutations (haploinsufficiency) and a dominant negative forms of mutations. Pedigrees with dominant negative missense mutation of the AML1 appear to have a higher insidence of development of AML than those in families with genuine haploinsufficiency of the AML1 gene such as deletions and frameshift mutations. These observations suggest that dosage of AML1 is critical for acquisition of second mutation leading to AML although this molecular mechanism remains to be determined. Methylation of the p15 gene, which is frequently observed in AML, is candidate for second mutation that should stimulate cell proliferation. We are analyzing p15 mRNA expression in AML by using quantitative assay with real-time RT-PCR. We have also examined mutations of the AML1 gene in patients with acute transformation from myelodysplastic syndrome and relapsing AML.

Runt结构域转录因子AML1/RUNX1对最终造血干细胞的产生和分化至关重要。AML1是急性白血病中染色体易位最常见的目标。一些嵌合蛋白如AML1- mtg8和TEL-AML1对野生型AML1具有跨显性特性，并作为转录抑制因子。另一方面，AML1的Runt结构域突变在没有AML1易位的散发性急性髓母细胞白血病（AML）和具有AML易感性的家族性血小板疾病（FPD/AML）中都被发现。在这项研究中，我们在25例（20%）AML M0亚型患者中发现了5例AML1基因突变。我们还在FPD/AML的2个血统中发现了AML1基因突变。这些观察结果表明，染色体易位或突变导致的AML1剂量减少有助于白血病的发生。FPD/AML谱系中AML1突变体的功能分析显示AML1基因的两种突变类型：功能缺失突变（单倍不足）和显性阴性突变形式。AML1显性负错义突变的家系似乎比AML1纯单倍缺陷（如缺失和移码突变）的家系有更高的AML发病几率。这些观察结果表明，AML1的剂量对于获得导致AML的第二突变至关重要，尽管其分子机制仍有待确定。在AML中经常观察到的p15基因甲基化是刺激细胞增殖的第二突变的候选基因。我们正在使用实时RT-PCR定量分析AML中p15 mRNA的表达。我们还研究了骨髓增生异常综合征和复发性AML急性转化患者的AML1基因突变。

项目成果

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Yokozawa T、Asou N 等人：“细胞周期抑制剂 p27Kip1 在急性髓系白血病中的预后意义。”白血病。

Hoshino K, Asou N, et al.: "The absence of the p15INK4B gene alterations in adult patients with precursor B-cell acute lymphoblastic leukaemia is a fovorable prognostic factor"Br J Haematol. (in press,発表予定). (2002)

Hoshino K、Asou N 等人：“前体 B 细胞急性淋巴细胞白血病成人患者中缺乏 p15INK4B 基因改变是一个有利的预后因素”Br J Haematol（出版中，待出版）。 ）

Takeshita A,Asou N, et al: "Quantitative expression of erythropoietin receptor (EPO-R) on acute leukaemia cells : relationships between the amount of EPO-R and CD phenotypes, in vitro proliferative response, the amount of other cytokine receptors and clin

Takeshita A、Asou N 等人：“急性白血病细胞上促红细胞生成素受体 (EPO-R) 的定量表达：EPO-R 的量与 CD 表型、体外增殖反应、其他细胞因子受体的量与临床的关系

Naoe T, Asou N, et al.: "Prognostic significance of the null genotype of glutathione S-transferase-T1 in patients with acute myeloid leukemia : increased early death after chemotherapy"Leukemia. 16. 203-208 (2002)

Naoe T、Asou N 等人：“急性髓系白血病患者中谷胱甘肽 S-转移酶-T1 无效基因型的预后意义：化疗后早期死亡增加”白血病。

Hoshino K, Asou N, et al.: "The absence of the p15INK4B gene alterations in adult patients with precursor B-cell acute lymphoblastic leukaemia is a favorable prognostic factor"Br J Haematol. (in press)(発表予定). (2002)

Hoshino K、Asou N 等人：“患有前体 B 细胞急性淋巴细胞白血病的成年患者中缺乏 p15INK4B 基因改变是一个有利的预后因素”Br J Haematol（出版中）。