GROWTH REGULATION IN AIDS RELATED LYMPHOMAS

艾滋病相关淋巴瘤的生长调节

• 批准号: 2108384
• 负责人: RICHARD J FORD
• 金额: $ 24.9万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-08-01 至 1997-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2108384
• 关键词: AIDS; B lymphocyte; SCID mouse; antisense nucleic acid; apoptosis; autocrine; biopsy; cell growth regulation; cell line; cell sorting; cyclosporines; cytogenetics; cytokine; growth factor; growth factor receptors; interleukin 6; molecular oncology; neoplasm /cancer immunology; neoplastic transformation; nonHodgkin's lymphoma; northern blottings; oncogenes; transfection; tumor suppressor genes; western blottings

AIDS-related lymphomas (ARL) are a group of immune deficiency-associated, aggressive B cell, non-Hodgkin's lymphomas (NHL-B). The incidence of ARL in the US is currently increasing, as AIDS patients live longer, and become at greater risk for the later consequences of immune compromise. The biology of ARL, that primarily results in the small non-cleaved cell (SNCC; Burkitt's (BL)) or Large cell (Immunoblastic) histo-types, seems to involve a number of the pathogenetic programs involved in aggressive NHL-B in the HIV negative patient population, However, the rapidity of development and the prodigious cell growth potential of ARL, suggests that additional genetic, biologic, or immune factors may be involved. The biologic or molecular basis of the aggressive malignant B cell growth in the ARL is unknown. ARL arises in the B lymphoid cell lineage, after the accumulation of a variable number of specific oncogene, viral, or tumor suppressor gene abnormalities that lead to cellular immortalization in NHL-B precursor cells. Studies will pursue our preliminary results that suggest that the immortalized, NHL precursor B cells, aberrantly express one or more of the BCGF (IL14, LMW-BCGF) cytokine genes, probably as part of the malignant transformation process. inappropriately expressed BCGF genes in ARL become autocrine growth factors (AGF) for the lymphoma cells, that also constitutively express the IL-I4R. Co-stimulatory factors for normal B cell proliferation, such the CD4O ligand (CD4OL) gp39, will also be evaluated for growth stimulatory potential in the ARL. Other cytokines with putative B cell stimulatory activity, such as IL6 or lL1O, will also be studied for a possible role in mediating or co-stimulating ARL cell growth in vitro. Since autocrine growth in the ARL appears to be mediated by BCGF molecules, we will explore methods for inhibiting cell growth thru growth factor deprivation, by inhibiting these cytokine growth factor genes in the ARL, with cytokine inhibitory drugs, such as cyclosporin A (CsA), and anti-sense oligonucleotides (ASO). Pathogenesis of the ARL will be explored in vitro, in experimental B cell models, containing transfected oncogenes and growth factor genes, that will be extended to in vivo studies, utilizing immune deficient. SCID mice. Finally, we will seek to identify additional (or different) genetic lesions in the ARL, possibly accounting for the accelerated development and/or aggressive clinical behavior, using comparative genomic hybridization (CGH), for identifying chromosomal abnormalities, not identifiable using conventional cytogenetic techniques.

艾滋病相关淋巴瘤 (ARL) 是一组与免疫缺陷相关的、 侵袭性 B 细胞，非霍奇金淋巴瘤 (NHL-B)。 ARL 的发生率 随着艾滋病患者寿命的延长，美国的艾滋病患者人数目前正在增加， 因免疫受损而导致后续后果的风险更大。 ARL 的生物学原理，主要产生小的未裂解细胞 （SNCC；伯基特 (BL)）或大细胞（免疫母细胞）组织类型，似乎 涉及侵袭性 NHL-B 的许多致病程序 然而，在 HIV 阴性患者群体中， ARL 的发育和巨大的细胞生长潜力表明 可能还涉及其他遗传、生物或免疫因素。这 侵袭性恶性 B 细胞生长的生物学或分子基础 ARL 未知。 ARL 出现在 B 淋巴细胞谱系中， 不同数量的特定癌基因、病毒或肿瘤的积累 导致细胞永生化的抑制基因异常 NHL-B 前体细胞。 研究将追求我们的初步结果 表明永生化的 NHL 前体 B 细胞异常表达 一种或多种 BCGF（IL14、LMW-BCGF）细胞因子基因，可能作为其一部分 的恶性转化过程。 BCGF表达不当 ARL 中的基因成为淋巴瘤细胞的自分泌生长因子 (AGF)， 其也组成型表达IL-I4R。 共刺激因素 正常的 B 细胞增殖，例如 CD4O 配体 (CD4OL) gp39，也会 评估 ARL 中的生长刺激潜力。 其他细胞因子 具有假定的 B 细胞刺激活性，例如 IL6 或 lL1O，也将 正在研究其在介导或共刺激 ARL 细胞中的可能作用 体外生长。 由于 ARL 中的自分泌生长似乎是介导的 通过BCGF分子，我们将探索通过BCGF分子抑制细胞生长的方法 生长因子剥夺，通过抑制这些细胞因子生长因子 ARL 中的基因，与细胞因子抑制药物，如环孢菌素 A (CsA) 和反义寡核苷酸 (ASO)。 ARL 的发病机制 将在体外实验 B 细胞模型中进行探索，其中包含 转染癌基因和生长因子基因，将扩展到 利用免疫缺陷进行体内研究。 SCID小鼠。最后，我们将寻求 识别 ARL 中额外的（或不同的）遗传损伤，可能 解释加速发展和/或积极的临床 行为，使用比较基因组杂交（CGH）来识别 染色体异常，使用传统的细胞遗传学无法识别 技术。