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在与t(4;11)(q21;q23)易位相关的双表型白血病SCID小鼠模型中白血病母细胞的BCL-2表达。

BCL-2 expression by leukaemic blasts in a SCID mouse model of biphenotypic leukaemia associated with the t(4;11)(q21;q23) translocation.

作者信息

Pocock C F, Malone M, Booth M, Evans M, Morgan G, Greil J, Cotter F E

机构信息

ICRF Oncology Group, Institute of Child Health, London.

出版信息

Br J Haematol. 1995 Aug;90(4):855-67. doi: 10.1111/j.1365-2141.1995.tb05207.x.

Abstract

Acute leukaemia of infancy is associated with abnormalities at chromosome band 11q23, and has a poor prognosis. The gene involved. Mixed Lineage Leukaemia (MLL), has been identified and has the characteristics of a transcription factor. The BCL-2 gene responsible for blocking of programmed cell death is highly expressed in a number of haematological malignancies, both with and without the t(14;18) translocation. Those without the translocation include acute lymphoblastic leukaemia (ALL), acute myeloid leukaemia (AML) and chronic lymphocytic leukaemia (CLL). In these diseases the BCL-2 protein is implicated in drug resistance to apoptosis-inducing chemotherapeutic agents. High BCL-2 expression is also associated with autonomous growth of leukaemic blasts in culture and predicts a poor prognosis. The SEM cell line, established using blood lymphoblasts from a 5-year-old girl in first relapse with t(4;11) ALL, expresses lymphoid (CD19) and myeloid (CD13) cell surface markers. In cell culture, a subpopulation of cells (< 30%) express the BCL-2 protein. A reproducible model of true biphenotypic leukaemia in the SCID mouse has been established using the SEM-K2 cell line (a subclone of the SEM cell line). Between 5 and 50 million cells injected intravenously (i.v.) produce complete replacement of the murine bone marrow by day 30, associated with blood lymphoblastosis and infiltration of the spleen. No tumour masses were seen. Fluorescence in situ hybridization (FISH) analysis of the cell line and blood from the SCID-human (SCID-hu) chimaera has confirmed the presence of the t(4;11). Reverse transcriptional-polymerase chain reaction (RT-PCR) reveals that the breakpoint lies between exons 7 and 8 of the MLL-1 gene on chromosome 11 (the main breakpoint region). A further translocation, t(7;13), has been identified. Fluorescent antibody cell sorter (FACS) analysis of tumour material recovered from the SCID-hu model confirms expression of CD19 and CD13 identical to that of the cell line. In addition, BCL-2 expression in SCID-hu marrow is now seen in the majority of tumour cells. BCL-2 expression appears to confer a survival advantage to the blast cells in vivo. This reproducible model of biphenotypic leukaemia suggests that BCL-2 expression may play a role in leukaemogenesis. The model is suitable for the investigation of gene-targeted therapy, including antisense oligonucleotides, directed towards the MLL and BCL-2 genes.

摘要

婴儿急性白血病与11q23染色体带异常有关,预后较差。所涉及的基因——混合谱系白血病(MLL)已被鉴定,具有转录因子的特征。负责阻断程序性细胞死亡的BCL-2基因在许多血液系统恶性肿瘤中高表达,无论有无t(14;18)易位。没有这种易位的疾病包括急性淋巴细胞白血病(ALL)、急性髓细胞白血病(AML)和慢性淋巴细胞白血病(CLL)。在这些疾病中,BCL-2蛋白与对诱导凋亡的化疗药物的耐药性有关。BCL-2高表达还与白血病原始细胞在培养中的自主生长有关,并预示预后不良。SEM细胞系是使用一名5岁首次复发t(4;11) ALL女孩的血液淋巴母细胞建立的,表达淋巴样(CD19)和髓样(CD13)细胞表面标志物。在细胞培养中,一小部分细胞(<30%)表达BCL-2蛋白。使用SEM-K2细胞系(SEM细胞系的一个亚克隆)在SCID小鼠中建立了一种可重复的真正双表型白血病模型。静脉注射(i.v.)500万至500万股细胞在第30天时可使小鼠骨髓完全被替代,伴有血液淋巴母细胞增多和脾脏浸润。未见肿瘤块。对该细胞系和SCID-人(SCID-hu)嵌合体血液进行荧光原位杂交(FISH)分析证实存在t(4;11)。逆转录聚合酶链反应(RT-PCR)显示断点位于11号染色体上MLL-1基因的外显子7和8之间(主要断点区域)。还发现了另一种易位,t(7;13)。对从SCID-hu模型中回收的肿瘤材料进行荧光抗体细胞分选仪(FACS)分析证实,CD19和CD13的表达与细胞系相同。此外,现在在大多数肿瘤细胞中都能看到SCID-hu骨髓中的BCL-2表达。BCL-2表达似乎赋予了原始细胞在体内的生存优势。这种可重复的双表型白血病模型表明,BCL-2表达可能在白血病发生中起作用。该模型适用于研究针对MLL和BCL-2基因的基因靶向治疗,包括反义寡核苷酸。

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