The role of newly cloned genes related to chromosome translocation on hematological differentiation and proliferation.

新克隆的染色体易位相关基因对血液分化和增殖的作用。

• 批准号: 05454337
• 负责人: UEDA Ryuzo
• 金额: $ 4.35万
• 依托单位: Nagoya City University (1995)Aichi Cancer Center Research Institute (1993-1994)
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for General Scientific Research (B)
• 财政年份: 1993
• 资助国家: 日本
• 起止时间: 1993 至 1995
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-05454337/
• 关键词: Hematopoietic malignancy; Chromosome translocation; MLL gene; PRAD1; BCL-lgene; Transgenic mouse; 5D4monoclonal antibody; Mantle cell lymphoma; Secondary leukemia; PRAD1遺伝子; マントル層リンパ腫の予後; マントル層リンパ腫; RCK遺伝子; PRADI遺伝子; BCL-1遺伝子

Chromosome translocation has been demonstrated to play an important role in the genesis of hematopoietic malignancies. We focused the translocation involving the chromosome 11 band q13 and q23.Recent studies of 11q13 region have shed light on the pathogenesis of mantle cell lymphoma and the translocation on region 11q23 has been recurrently observed in various types of hematopoietic malignancies. Such as malignant lymphoma, acute promyelocytic leukemia, infantile leukemia and secondary leukemia occurring after chemotherapy.Regarding 11q13 region, we proved the identity between BCL-1 and the PRAD1/cyclin D1 gene based on our analyzes of the PRAD1 transcripts and the breakpoint region of the variant translocation case. Recently, we produced a monoclonal antibody, 5D4, against the PRAD1/cyclin D1 product and demonstrated specific positive nuclear staining to be associated with mantle cell lymphoma (MCL). According to the data of immunostaining obtained from 334 cases of hematological diso … More rders including 39 cases of MCL,the MCL showed the poorest prognosis among them.We cloned and characterize the two genes from the 11q23 region, and named MLL and PCK/P54 genes, respectively. Regarding MLL gene, which encodes a 3969 amino acid polypeptide homologous to Drosophila trithorax, containing two putative DNA-binding motifs consisting of three AT-hook motifs and two multiple zinc finger domains. Almost all the breakpoints in acute leukemia with 11q23 translocations lie in a cluster region on the MLL gene. We established the reverse trascriptase-polymerase chain reaction (RT-PCR). Sensitivity studies showed that a single clone with cheimeric mRNA in 10^4 to 10^5 cells could be detected. This RUT-PER method provide a rapid, accurate, and sensitive tool for diagnosing leukemia wtih 11q23 translocation and for monitoring response to therapy in these patients.Recent our analyzes of function of MLL gene show the data thate the N-terminal portion of this gene, may play an important role on tumorigeneses and differentiation. Furthermore we produced the MLL transgenic mice in our laboratory, we have observed them more than one and half year. No tumor bearing mouse was observed, so far. Less

染色体易位已被证明在造血系统恶性肿瘤的发生中起重要作用。我们重点研究了涉及11号染色体q13和q23带的易位。最近对11q13区域的研究揭示了套细胞淋巴瘤的发病机制，11q23区域的易位在各种类型的造血恶性肿瘤中反复观察到。如恶性淋巴瘤、急性早幼粒细胞白血病、婴儿白血病及化疗后发生的继发性白血病。关于11q13区域，我们通过分析PRAD1转录本和变异易位病例的断点区域，证明了BCL-1与PRAD1/cyclin D1基因的同源性。最近，我们生产了一种针对PRAD1/cyclin D1产物的单克隆抗体5D4，并证明了与套细胞淋巴瘤（MCL）相关的特异性阳性核染色。根据334例血液病患者的免疫染色资料，其中MCL 39例，其中MCL预后最差。我们从11q23区域克隆并鉴定了这两个基因，并分别命名为MLL和PCK/P54基因。MLL基因编码一个3969个氨基酸的多肽，与三胸果蝇同源，包含两个推测的dna结合基序，包括三个AT-hook基序和两个多个锌指结构域。在11q23易位的急性白血病中，几乎所有的断点都位于MLL基因的一个簇状区域。我们建立了逆转录酶-聚合酶链反应（RT-PCR）。敏感性研究表明，可以在10^4到10^5个细胞中检测到具有化学mRNA的单克隆。这种rt - per方法为诊断11q23易位白血病和监测这些患者对治疗的反应提供了一种快速、准确和敏感的工具。最近我们对MLL基因的功能分析表明，该基因的n端部分可能在肿瘤发生和分化中起重要作用。此外，我们在实验室培育了MLL转基因小鼠，并对其进行了一年半以上的观察。到目前为止，未观察到荷瘤小鼠。少

项目成果

Kagami,Y.: "Novel interleukin-2 dependent T-cell line derived from adult T-cell leukemia not associated with human T-cell leukemia virus type 1." Jpn. J. Cancer Res.84. 532-537 (1993)

Kagami,Y.：“源自成人 T 细胞白血病的新型白细胞介素 2 依赖性 T 细胞系，与人类 T 细胞白血病病毒 1 型无关。”

Iida,S.: "MLLT3 gene on 9p22 involved in t(9;11) leukemia encodes a serine/proline rich protein homologous to MLLT1 on 19p13." Oncogene. 8. 3085-3092 (1993)

Iida,S.：“参与 t(9;11) 白血病的 9p22 上的 MLLT3 基因编码与 19p13 上的 MLLT1 同源的富含丝氨酸/脯氨酸的蛋白质。”

Namikawa,R.: "Growth of human myeloid leukemias in the human marrow environment of SCID-hu mice." Blood. 82. 2526-2536 (1993)

Namikawa,R.：“SCID-hu 小鼠的人类骨髓环境中人类髓系白血病的生长。”

Iida,S.: "Molecular cloning of 19p13 breakpoint region in intanfile leukemia with t(11;19)(q23;p13)translocation." Jpn.J.Cancer Re.84. 532-537 (1993)

Iida,S.：“具有 t(11;19)(q23;p13) 易位的 intanfile 白血病 19p13 断点区域的分子克隆。”

Hattori, K.: "Bispecific antibody-mediated cytotoxicity by CD24^+ and CD28^+-activated T cells generated from leukemia patients after allogeneic bone marrow transplantation." Bone Marrow Transplantation. 15. 193-198 (1994)

Hattori, K.：“同种异体骨髓移植后白血病患者产生的 CD24^ 和 CD28^ 激活 T 细胞介导的双特异性抗体介导的细胞毒性。”