Identification of a novel tumor suppressor gene in lymphoid neoplasms

淋巴肿瘤中新型抑癌基因的鉴定

• 批准号: 11670990
• 负责人: KINOSHITA Tomohiro
• 金额: $ 2.24万
• 依托单位: Nagoya University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1999
• 资助国家: 日本
• 起止时间: 1999 至 2000
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-11670990/
• 关键词: MALIGNANT LYMPHOMA; TUMOR SUPPRESSOR GENE; CHROMOSOME; 6p; 1q; PROX1; DNA METHYLATION; リンパ系腫瘍

We have identified frequent loss of heterozygosity (LOH) at 1q, 3p, 6p, and 6q in B-cell non-Hodgkin lymphomaby allelotype studies. We have conducted fine deletion mapping on 6p and identified two common deleted regions, one is between D6S1721 and D6S260 (at 6p23-24), and the other between D6S265 and D6S291 (at 6p21). Next we started a search for a novel tumor suppressor gene on 1q. PROX1, a homologue of Drosophilla homeobox gene, is located on chromosome 1q32, which is a common chromosomal deleted lesion in malignant lymphoma that we have identified. Although PROX1 mRNA is ubiquitously expressed in normal hematolymphoid systems, it was not expressed in several hematolymphoid cell lines. PROX1 expression in Raji cell was not detected by RT-PCR method, but it was restored after 5-AzaC treatment. Nucleotide sequence analysis after bisulfite modification revealed that PROX1 expression in hematolymphoid cell lines and normal peripheral blood mononuclear cells was correlated very well with hypermethylation in intron 1 of PROX1 gene. Mutational analyses of PROX1 gene have revealed 6 missence and/or nonsense mutations in 5 cell lines (BALL1, HEL, THP6, RPMI8402 and Jurkat). These results indicated that PROX1 is inactivated in several hematolymphoid neoplasms, mainly by DNA methylation. These results strongly suggested that PROX1 is a novel candidate for tumor suppressor gene that is related to hematolymhoid neoplasms. Since PROX1 function as a tumor suppressor is still uncertain, we are now evaluating PROX1 functions on cellular growth or transformation.

我们在 B 细胞非霍奇金淋巴瘤等位基因型研究中发现了 1q、3p、6p 和 6q 频繁杂合性丢失 (LOH)。我们对6p进行了精细的删除映射，确定了两个常见的删除区域，一个位于D6S1721和D6S260之间（位于6p23-24），另一个位于D6S265和D6S291之间（位于6p21）。接下来我们开始在 1q 上寻找一种新的抑癌基因。 PROX1是果蝇同源盒基因的同源物，位于染色体1q32上，是我们已发现的恶性淋巴瘤中常见的染色体缺失病变。尽管 PROX1 mRNA 在正常血淋巴系统中普遍表达，但在几种血淋巴细胞系中并不表达。 RT-PCR方法未检测到Raji细胞中PROX1的表达，但5-AzaC处理后恢复。亚硫酸氢盐修饰后的核苷酸序列分析表明，造血淋巴细胞系和正常外周血单个核细胞中 PROX1 的表达与 PROX1 基因内含子 1 的高甲基化密切相关。 PROX1 基因的突变分析揭示了 5 个细胞系（BALL1、HEL、THP6、RPMI8402 和 Jurkat）中的 6 个错义和/或无义突变。这些结果表明 PROX1 在几种造血淋巴肿瘤中主要通过 DNA 甲基化失活。这些结果强烈表明PROX1是与血淋巴肿瘤相关的抑癌基因的新候选者。由于 PROX1 作为肿瘤抑制因子的功能仍不确定，我们现在正在评估 PROX1 对细胞生长或转化的功能。

项目成果

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H.Suzuki 等人：“环形铁粒幼细胞难治性贫血的克隆性分析：骨髓祖细胞克隆性和细胞化学的同步研究。”白血病。

A.Tomita: "c-Myb acetylation at the carboxyl-terminally conserved domain by transcriptional co-activator p300."Oncogene. 19. 444-451 (2000)

A.Tomita：“转录共激活因子 p300 在羧基末端保守结构域处对 c-Myb 进行乙酰化。”癌基因。

H.Kosugi et al.: "Histone deacetylase inhibitors are the potent inducer/enhancer of differentiation in acute myeloid leukemia : a new approach to anti-leukemia therapy."Leukemia. 13. 1316-1324 (1999)

H.Kosugi 等人：“组蛋白脱乙酰酶抑制剂是急性髓系白血病分化的有效诱导剂/增强剂：一种抗白血病治疗的新方法。”白血病。

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Y.Nakahara：“通过基于 PCR 的 HUMARA 方法对健康女性的粒细胞和 T 淋巴细胞进行克隆性分析。”Int.J.Hematol.. 69. 237-243 (1999)

H.Kosugi: "Histone deacetylase inhibitors are the potent inducer/enhancer of differentiation in acute myeloid leukemia : a new approach to anti-leukemia therapy."Leukemia. 13. 1316-1324 (1999)

H.Kosugi：“组蛋白脱乙酰酶抑制剂是急性髓系白血病分化的有效诱导剂/增强剂：一种抗白血病治疗的新方法。”白血病。