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

人类T细胞白血病病毒I型（HTLV-I）感染后，在发生成人T细胞白血病（ATL）之前有很长的潜伏期，我研究了白血病发生的分子机制以及ATL的发病机制。 1）首先在p16基因的外显子中检测到DNA甲基化，然后进展到启动子区域。当启动子区域被甲基化时，我们发现DNA的转录被沉默。 5'长末端重复序列（LTR）的甲基化使病毒基因转录沉默。在原病毒内，DNA甲基化首先发生在内部区域，例如gag、pol和env区域，然后扩散到5'和3'方向。通过甲基化 CpG 岛扩增/代表性差异分析 (MCA/RDA) 分离出 ATL 细胞中的异常甲基化 DNA 区域，并将 MEL1S 基因鉴定为 ATL 细胞中的低甲基化基因。在ATL细胞中观察到MEL1S基因的异常表达，这使得ATL细胞能够抵抗TGF-β，因此，MEL1S的表达被认为是赋予KLF4抵抗的机制之一。研究发现，EGR3 基因在 ATL 细胞中高度甲基化，沉默的 EGR3 基因转录会导致 Fas 配体表达丧失，从而使 ATL 细胞能够逃避 Fas-Fas 配体的诱导。 2）发现来自高钙血症患者的ATL细胞在其表面表达RANK配体并产生M-CSF，并且M-CSF已显示出协同诱导造血前体细胞从高钙血症分化为ATL细胞。 3)在HTLV-I感染者和ATL患者中观察到免疫缺陷状态，我们分析了幼稚和记忆T细胞亚群。 HTLV-I 携带者和 ATL 患者，发现 HTLV-I 感染者的幼稚 T 细胞数量减少，因为 HTLV-I 感染者的 T 细胞受体切除圈减少，因此认为幼稚 T 细胞减少。 4) Tax 表达在 ATL 细胞中经常丢失。我们确定了 Tax 表达失活的三种机制：1) Tax 基因的遗传变化，2) Tax 基因的 DNA 甲基化。 5'-LTR 和 3) 5'-LTR 缺失。

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.