Molecular mechanisms of leukemogenesis and pathogenesis in adult T-cell leukemia

成人T细胞白血病白血病发生和发病机制的分子机制

• 批准号: 12213057
• 负责人: MATSUOKA Kasao
• 金额: $ 27.65万
• 依托单位: 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: 2000
• 资助国家: 日本
• 起止时间: 2000 至 2004
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-12213057/
• 关键词: Adult T-cell leukemia; Retrovirus; Oncogenesis; HTLV-I; Methylation; Leukemogenesis; アポトーシス; 抗体療法; Fas; ヒト細胞性白血病ウイルス; 白血病; メチル化; p53; ヒト白血病ウイルスI型; 高カルシウム血症; 免疫不全; ナイープTリンパ球

After infection of human T-cell leukemia virus type I (HTLV-I), there is a long latent period before the onset of adult T-cell leukemia (ATL). I have studied the molecular mechanisms of leukemogenesis, and pathogenesis in ATL.1) DNA methylation was first detected in the exon of p16 gene, and then it progressed to the promoter region. When the promoter region was methylated, the transcription of p16 gene was silenced. We found that DNA methylation of 5'-long terminal repeat (LTR) silenced the viral gene transcription. Within provirus, DNA methylation first occurred in the internal regions, such as gag, pol and env regions, and then spread to 5' and 3' directions. We isolated the aberrant methylated DNA regions in ATL cells by Methylated CpG island amplification/representative difference assay (MCA/RDA). MEL1S gene was identified as hypomethylated one in ATL cells. Aberrant expression of MEL1S gene was observed in ATL cells, which enabled ATL cells resistant to TGF-β. Therefore, MEL1S ex … More pression is considered to be one of mechanisms to confer the resistance to TGF-β. On the other hand, KLF4 and EGR3 genes were found to be hypermethylated in ATL cells. Silenced EGR3 gene transcription results in loss of Fas ligand expression, which enables ATL cells to escape from Fas-Fas ligand induced apoptosis.2) ATL cells from hypercalcemic patients were found to express RANK ligand on their surfaces and produce M-CSF. RANK ligand and M-CSF have shown to co-operatively induce the differentiation of hematopoietic precursor cells into osteolcast. ATL cells from hypercalcemic patients could induce the differentiation to osteoclast in vitro.3) Immunodeficiet state is observed in HTLV-I infected individuals and ATL patients. We analyzed the naive and memory T-cell subpopulation among HTLV-I carriers and ATL patients, and found that the number of naive T-cell decreased in HTLV-I infected individuals. Since T-cell receptor excision circles were decreased in HTLV-I infected individuals, decreased naive T-cell is thought to be due to suppressed production in the thymus.4) Tax expression is frequently lost in ATL cells. We identified three mechanisms in inactivation of Tax expression : 1) genetic changes of tax gene, 2) DNA methylation of 5'-LTR and 3) deletion of 5'-LTR. Less

感染人类T细胞白血病I型（HTLV-I）后，成年T细胞白血病（ATL）发作之前有一个长期的潜在时期。我已经研究了白血病发生的分子机制，在ATL.1）DNA甲基化中首先在p16基因的外显子中检测到DNA甲基化，然后发展为启动子区域。当启动子区域被甲基化时，p16基因的转录被沉默。我们发现5'长末端重复（LTR）的DNA甲基化沉默了病毒基因转录。在病毒中，DNA甲基化首先发生在内部区域，例如GAG，POL和Envires，然后扩散到5'和3'方向。我们通过甲基化的CpG岛扩增/代表性差异测定法（MCA/RDA）分离了ATL细胞中ATL细胞中异常的甲基化DNA区域。 MEL1S基因被鉴定为ATL细胞中的降甲基化基因。在ATL细胞中观察到MEL1S基因的异常表达，这使ATL细胞能够抗TGF-β。因此，MEL1S EX…更大的压力被认为是赋予TGF-β抗性的机制之一。另一方面，发现KLF4和EGR3基因在ATL细胞中是高甲基化的。沉默的Egr3基因转录导致FAS配体表达丧失，这使ATL细胞从FAS-FAS配体诱导的凋亡中逃脱。2）来自高钙血症患者的ATL细胞在其表面上表达了秩配体并产生的M-CSF。等级配体和M-CSF已证明可以合作地诱导造血前体细胞分化为骨醇。来自高钙血症患者的ATL细胞可以在体外诱导与破骨细胞的分化。3）在HTLV-I感染的个体和ATL患者中观察到免疫缺陷态。我们分析了HTLV-I载体和ATL患者之间的天真和记忆T细胞亚群，发现HTLV-I感染个体的天真T细胞数量减少。由于HTLV-I感染个体的T细胞受体惊喜电路降低，因此人们认为幼稚的T细胞降低是由于胸腺中抑制的产生。4）ATL细胞中经常损失税收表达。我们确定了税表达灭活的三种机制：1）税收基因的遗传变化，2）5'-LTR的DNA甲基化和3）5'-LTR的缺失。较少的

项目成果

Mechanism of hypercalcemia in adult T-cell leukemia : Overexpression of RANK ligand on adult T-cell leukemia.

成人 T 细胞白血病高钙血症的机制：成人 T 细胞白血病中 RANK 配体的过度表达。

• 发表时间: 2002
• 期刊: Blood 99
• 作者: Yasunaga J-I.;Yoshida M.;Takeda S.;Yasunaga J-I.;Satou Y.;Okayama A.;M Yasunaga J-I.;Matsuoka M.;Matsuoka M.;Nishimura M.;Yasunaga J-I.;Nosaka K.
• 通讯作者: Nosaka K.

Tamamura H: "Development of specific CXCR4 inhibitors possessing high selectivity indexes as well as complete stability in serum based on an anti-HIV peptide T140"Bioorg Med Chem Lett.. 11. 1897-1902 (2001)

Tamamura H：“基于抗 HIV 肽 T140 开发具有高选择性指数以及血清中完全稳定性的特异性 CXCR4 抑制剂”Bioorg Med Chem Lett.. 11. 1897-1902 (2001)

Nosaka, K.: "Mechanism of hypercalcemia in adult T-cell leukemia : Overexpression of RANK ligand on adult T-cell leukemia"Blood. 99. 634-640 (2002)

Nosaka, K.：“成人 T 细胞白血病高钙血症的机制：成人 T 细胞白血病上 RANK 配体的过度表达”血液。

Sakai T: "Missense mutation of interleukin 12 receptor b1 chain gene is associated with impaired cell mediated immunity against Mycobacterium Avium complex"Blood. 97. 2688-2694 (2001)

Sakai T：“白细胞介素 12 受体 b1 链基因的错义突变与细胞介导的针对鸟分枝杆菌复合体的免疫受损有关”血液。

Somatic alterrations of adult T cell leukaemia cells.

成人 T 细胞白血病细胞的体细胞改变。

• 发表时间: 2004
• 期刊: Leukaemia and Lymphoma 12
• 作者: Yasunaga J-I.;Yoshida M.;Takeda S.;Yasunaga J-I.;Satou Y.;Okayama A.;M Yasunaga J-I.;Matsuoka M.
• 通讯作者: Matsuoka M.