Chromosomal translocations deregulating <I>c-myc</I>

B细胞恶性肿瘤，如Burkitt淋巴瘤(BL)、艾滋病相关的非霍奇金淋巴瘤(AIDS-NHL)、弥漫性大细胞B淋巴瘤(DLCL)和小鼠浆细胞瘤(PC)，呈现出一种特征性的非随机染色体易位，这种易位往往导致c-myc的结构性表达，c-myc是细胞增殖的重要调节因子。为了重新控制这些B细胞恶性肿瘤中c-myc的表达，我们一直在研究表达不同水平c-myc的等位基因多态。这种方法背后的原理是基于我们实验室最近的一项发现，即某些人类c-myc等位基因在表达上存在缺陷，导致基本上单一野生型等位基因的单等位基因表达。包括CAA-33、S11N和K288S在内的等位基因变异最初是通过基于PCR的SSCP分析在NIH血库对正常健康志愿者进行大规模筛查而确定的。虽然S11N和K288S等位基因在高加索人群中是内源性的，但CAA-33等位基因几乎只在非洲人或非裔美国人中发现。K288S和CAA-33等位基因在外周血中都被发现转录受损。在基因水平的详细研究进一步表明，CAA-33等位基因与c-myc的5‘非翻译区(5’UT)的第二个多态改变有关。由于转录活性的丧失似乎与这种5‘UT多态有关，我们的研究现在正致力于确定哪些转录调控分子可能与该区域结合。

B cell malignancies such as Burkitt's lymphoma (BL), AIDS-associated non-Hodgkins lymphoma (AIDS-NHL), Diffuse Large Cell B lymphomas (DLCL) and the mouse plasmacytoma (PC) present with a characteristic non-random chromosomal translocation that often results in the constitutive expression of c-MYC, an important regulator of cellular proliferation. In an attempt to regain control of c-MYC expression in these B cell malignancies, we have been studying allelic polymorphisms that express differing levels of c-MYC. The rationale behind this approach resides on a recent discovery in our laboratory that certain human c-MYC alleles are defective in expression leading to essentially monoallelic expression of a single wildtype allele. The allelic variants including CAA-33, S11N and K288S, were originally identified through a large screening of normal healthy volunteers at the NIH Blood Bank by a PCR-based SSCP assay. While the S11N and K288S alleles are endogenous to the Caucasian population, the CAA-33 allele is found almost exclusively in African or African-Americans. Both the K288S and CAA-33 alleles are found to be transcriptionally compromised in peripheral blood. Detailed studies at the gene level reveal further that the CAA-33 allele is associated with a second polymorphic change in the 5' untranslated region (5'UT) of c-MYC. Since it appears that loss of transcriptional activity is linked to this 5' UT polymorphism, our studies are now directed towards determining what transcriptional regulating molecules may bind to this region.