Mechanisms of leukemogenesis caused by alterations of the structure of transcription factor PEBP2

转录因子PEBP2结构改变引起的白血病发生机制

• 批准号: 09253220
• 负责人: ITO Yoshiaki
• 金额: $ 48万
• 依托单位: Institute for Virus Research, Kyoto University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research on Priority Areas
• 财政年份: 1994
• 资助国家: 日本
• 起止时间: 1994 至 1999
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-09253220/
• 关键词: RUNX1; RUNX2; RUNX3; AML1; PEBP2; FPD-AML; TGF-β; BMP; 急性骨髄性白血病; 点突然変異; ヘテロ変異体; 血管内皮細胞; G-CSF; FPD; AML; 転写因子; CBF; 発がん機構; キメラ遺伝子; 転写制御機構; ETO(MTG8); 32Dc13

Transcription factor PEBP2 is composed of α and β subunits. There are three genes encoding the α subunit, RUNX1/AML1, RUNX2/CBFA1, RUNX3/PEBP2αC.We found that RUNX1 is required for generation of hematopoietic stem cells from endothelial cells. RUNX1 is the most frequent target of chromosome translocations associated with acute leukemia but we found sporadic loss-of-function point mutations without involving chimeric proteins. Later, familial cases of point mutations were reported which are called Familial Patelet Disorder with Predisposition to Acute Myeloid Leukemia (FPD-AML). Mice carrying heterozygously disrupted RUNX1 gene were found to be a good mouse model for FPD-AML.Haploinsufficiency of RUNX1 is being proved to be leukemogenic.RUNX2 is essential for maturation of chondrocytes and osteoblasts. Haploinsufficiency of RUNX2 causes cleidocranial dysplasia (CCD). We found that RUNX2 is one of the major target of TGF-β/BMP signaling and mutations of RUNX2 impaired the BMP pathway to cause CCD.We found that RUNX3 was expressed in epithelial cells of gastrointestinal tractand that the disruption of the gene caused hyperplasia of epithelial layer of glandular stomach. Possible involvement of RUNX3 in gastric cancer is being studied.

转录因子PEBP 2由α和β亚基组成。RUNX 1/AML 1、RUNX 2/CBFA 1、RUNX 3/PEBP 2 αC是内皮细胞向造血干细胞分化的关键基因。RUNX 1是与急性白血病相关的染色体易位的最常见靶点，但我们发现了不涉及嵌合蛋白的零星功能丧失点突变。后来，报告了点突变的家族性病例，称为家族性髌骨疾病伴急性髓性白血病易感性（FPD-AML）。RUNX 1基因突变的小鼠是FPD-AML的良好模型，RUNX 1单倍不足与白血病的发生有关，RUNX 2基因突变对软骨细胞和成骨细胞的成熟至关重要。RUNX 2的单倍不足导致锁骨颅骨发育不良（CCD）。我们发现RUNX 2是TGF-β/BMP信号通路的主要靶点之一，RUNX 2基因突变后破坏BMP信号通路导致CCD的发生，RUNX 3基因在胃肠道上皮细胞中表达，RUNX 3基因突变后引起腺胃上皮细胞增生。RUNX 3在胃癌中的可能参与正在研究中。

项目成果

Nagata, T.: "Immunoglobulin motif DNA recognition and heterodimerization for the PEBP2/CBF Runt-domain"Nature struct. Biol.. 6. 615-619 (1999)

Nagata, T.：“PEBP2/CBF Runt 结构域的免疫球蛋白基序 DNA 识别和异二聚化”自然结构。

Tsuji,K.: "Expression of the PEBP2αA/AML3/CBFA1 genes is Regulated by BMP4/7 heterodimer and its overexpression suppresses type I collagen and osteocalcin gene expression in osteoblastic and nonosteoblastic mesenchymal cells." Bone. 22. 87-92 (1998)

Tsuji, K.：“PEBP2αA/AML3/CBFA1 基因的表达受 BMP4/7 异二聚体的调节，其过度表达会抑制成骨细胞和非成骨细胞间充质细胞中的 I 型胶原蛋白和骨钙素基因表达。” ）

Kanno,T.: "Intrinsic transcriptional activation/inhibition domains of the PEBP2/CBF α subunit revealed in the presence of the β subunit." Mol.Cell.Biol.18. 2444-2454 (1999)

Kanno, T.：“PEBP2/CBF α 亚基的内在转录激活/抑制结构域在 β 亚基存在下揭示。”Mol.Cell.Biol.18（1999）。

Morii, E.: "Identification of the region of transcription factor which is responsible for the Synergy with PEBP2/CBF"Biochem. Biophys. Res. Commu.. 261. 53-57 (1999)

Morii, E.：“鉴定负责与 PEBP2/CBF 协同作用的转录因子区域”Biochem。

Li,J.: "Smad2 overexpression enhances Smad4 gene expression and suppresses CBFA1 gene expression on osteoblastic osteosarcoma ROSI7/2.8 cells." J.Biological Chem.273. 31009-31015 (1998)

Li,J.：“在成骨性骨肉瘤 ROSI7/2.8 细胞上，Smad2 过表达可增强 Smad4 基因表达并抑制 CBFA1 基因表达。”