Analysis of the mechanism of leukemogenesis in leukemia cells carrying mutation of AML1 and PEBP2β genes

AML1和PEBP2β基因突变的白血病细胞白血病发生机制分析

• 批准号: 10670958
• 负责人: ASOU Norio
• 金额: $ 2.11万
• 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: 1998
• 资助国家: 日本
• 起止时间: 1998 至 1999
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-10670958/
• 关键词: acute myeloblastic leukemia; AML1 gene; point mutation; transcriptional factor; runt family; PEBP2β; mechanism of leukemogenesis; AML1-MTG8 fusion gene; MTG8融合遺伝子; ルント領域

The AML1 gene is known as the most frequent target of chromosomal translocations associated with leukemia. It encodes the α-subunit in the Runt domain family of heterodimeric transcriptional factors and acts to regulate the expression of various gene specific to hematopoiesis. The Translocations involving AML1 produce chimeric proteins such as AML1-ETO (MTG8) in acute myeloblastic leukemia (AML) with t(8;21)(q22;q22) and ETV6 (TEL)-AML1 in pediatric acute lymphoblastic leukemia(ALL)with t(12;21). A11 of these chimeric proteins retain thc entire Runt domain which is responsible for DNA binding and heterodimerization withβsubunit (PEBP2β). We round point mutations of the AML1 gene in 8 of 160 leukemias; 2 silent mutations, 4 heterozygous missense mutations, and 2 biallelic nonsense or frameshift mutations. Missense mutations in 3 patients showed neither DNA binding nor transactivation. The biallelic nonsense mutants encoding truncated AML1 proteins lost almost all functions and may play a role in leukemogenesis leading to AML. On the other hand,we found no mutation of the PEBP2βgene in 120 leukemias. In this study, we also examined mutation of the AML1 gene in AML M0 subtype to verify relationship between subtype and the AML1 gene mutation. In 6 of 30 patients with M0, we detected frameshift mutations of the AML1 gene, resulting in haploinsufficiency of the AML1. It was recently demonstrated that haploinsufficiency of AML1 causes familial platelet disorder associated with propensity to develop AML. Therefore, the haploinsufficiency of the AML1 is relevant to the predisposition or progression of leukemia.

AML 1基因被认为是与白血病相关的染色体易位最常见的靶点。它编码异源二聚体转录因子Runt结构域家族中的α亚基，并调节造血特异性的各种基因的表达。涉及AML 1的易位产生嵌合蛋白，如t（8;21）（q22;q22）的急性髓细胞白血病（AML）中的AML 1-ETO（MTG 8）和t（12;21）的儿科急性淋巴细胞白血病（ALL）中的ETV 6（TEL）-AML 1。这些嵌合蛋白中的所有11个都保留了负责DNA结合和与β亚基（PEBP 2 β）异源二聚化的完整Runt结构域。我们在160例白血病中的8例中发现了AML 1基因的点突变; 2例沉默突变，4例杂合错义突变，2例双等位基因无义突变或移码突变。错义突变3例，既没有DNA结合，也没有反式激活。编码截短的AML 1蛋白的双等位基因无义突变体几乎丧失了所有功能，并且可能在导致AML的白血病发生中发挥作用。另一方面，我们在120例白血病中未发现PEBP 2 β基因突变。本研究还检测了AML M0亚型中AML 1基因的突变，以验证亚型与AML 1基因突变的关系。在30例M0患者中的6例中，我们检测到AML 1基因的移码突变，导致AML 1的单倍不足。最近证实AML 1的单倍不足导致与发展AML的倾向相关的家族性血小板疾病。因此，AML 1的单倍不足与白血病的易感性或进展有关。

项目成果

Asou N, Suzushima H, Nishimura S, Okubo T, Yamasaki H, Osato M, Hoshino K, Takatsuki K, Mitsuya H: "Long-term remission in an elderly patient with mantle cell leukemia treated with low-dose cyclophosphamide"Am. J. Hematol. 63. 35-37 (2000)

Asou N、Suzushima H、Nishimura S、Okubo T、Yamasaki H、Osato M、Hoshino K、Takatsuki K、Mitsuya H：“低剂量环磷酰胺治疗老年套细胞白血病患者的长期缓解”Am。

Asou N,他8名: "Long-term remission in an elderly patient with mantle cell leukemia treated with low-dose cyclophosphamide."Am.J.Hematol.. 63. 35-37 (2000)

Asou N 和其他 8 人：“用低剂量环磷酰胺治疗老年套细胞白血病患者的长期缓解。”Am.J.Hematol.. 63. 35-37 (2000)

Kiyoi H,他17名: "Prognostic implication of FLT3 and N-RAS gene mutations in acute myeloid leudemia."Blood. 93. 3074-3080 (1999)

Kiyoi H 等人 17：“FLT3 和 N-RAS 基因突变对急性髓性白血病的预后影响。”Blood. 93. 3074-3080 (1999)

Asou N,et al.: "Acute myelomonoblastic leukemia carrying the PEBP2β/MYH11 fusion gene." Leukemia Lymphoma. vol31. 81-91 (1998)

Asou N 等人：“携带 PEBP2β/MYH11 融合基因的急性粒细胞白血病”，第 31 卷《白血病淋巴瘤》。

Yagasaki F, Jinnai I, Yoshida S, Yokoyama Y, Matsuda A, Kusumoto S, Kobayashi H, Terasaki H, Ohyashiki K, Asou N, Murohashi I, Bessho M, Hirashima K: "Fusion of TEL/ETV6 to a novel ACS2 in myelodysplastic syndrome and acute myelogenous leukemia with t(5;1

Yagasaki F、Jinnai I、Yoshida S、Yokoyama Y、Matsuda A、Kusumoto S、Kobayashi H、Terasaki H、Ohyashiki K、Asou N、Murohashi I、Bessho M、Hirashima K：“TEL/ETV6 与小说 ACS2 的融合