GROWTH REGULATION IN AIDS RELATED LYMPHOMAS

艾滋病相关淋巴瘤(ARL)是一组免疫缺陷相关的、 侵袭性B细胞非霍奇金淋巴瘤(NHL-B)。急性呼吸窘迫综合征的发病率 目前在美国，随着艾滋病患者寿命的延长， 将面临更大的风险，以应对免疫妥协的后续后果。 ARL的生物学，主要导致小的未分裂的细胞 (SNCC；Burkitt‘s(BL))或大细胞(免疫母细胞)组织型，似乎 涉及侵袭性非霍奇金淋巴瘤B细胞的多种致病程序 然而，在艾滋病毒阴性的患者群体中， ARL的发展和巨大的细胞生长潜力表明 可能涉及其他遗传、生物或免疫因素。这个 侵袭性恶性B细胞生长的生物学或分子基础 ARL是未知的。ARL出现在B淋巴样细胞谱系中，在 积聚数量可变的特定癌基因、病毒或肿瘤 导致细胞永生化的抑制基因异常 NHL-B前体细胞。研究将继续我们的初步结果，即 提示永生化的NHL前体B细胞异常表达 一个或多个BCGF(IL14，LMW-BCGF)细胞因子基因，可能是 恶变的过程。表达不当的BCGF ARL中的基因成为淋巴瘤细胞的自分泌生长因子(AGF)， 也能结构性地表达IL-I4R。共同刺激因素 正常的B细胞增殖，如CD4O配体(CD4OL)gp39，也会 在ARL中接受生长刺激潜力的评估。其他细胞因子 具有假定的B细胞刺激活性，如IL6或1L10，也将 研究其在调节或共刺激ARL细胞中的可能作用 在体外生长。由于ARL中的自分泌生长似乎是由 通过BCGF分子，我们将探索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，以及细胞因子抑制药物，如环孢素A (CsA)和反义寡核苷酸(ASO)。急性淋巴细胞性白血病的发病机制 将在体外探索，在实验的B细胞模型中，包含 转染癌基因和生长因子基因，将扩展到 体内研究，利用免疫缺陷。SCID小鼠。最后，我们将寻求 识别ARL中的其他(或不同)遗传损伤，可能 加速发展和/或进攻性临床 行为，使用比较基因组杂交(CGH)来识别 用常规细胞遗传学无法识别的染色体异常 技巧。

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.