CHROMOSOME ABNORMALITIES AND HUMAN LEUKEMIA AND LYMPHOMA

长期目标是确定遗传变化的性质 是由人类白血病中反复出现的染色体畸变引起的。 这包括克隆结构染色体的断裂点 重排（例如易位、倒位等）和识别 基因受这些要求的影响。 一旦基因被克隆， 白血病细胞中的正常功能和它们改变的功能， 测定 我们在CLL的t（14;19）染色体19 q13上克隆了一个新基因BCL 3， 正在研究它的功能和调节。 我们克隆了 t（1;7）（p34;q34），并已确定1号染色体上的基因为LCK， 淋巴细胞特异性酪氨酸激酶 LCK的两个5'启动子被分开 3 ′启动子与T细胞受体β相邻。 我们目前正在克隆四个易位中的断点， 11q23 [t（4;11），t（6;11），t（9;11）and t（11;19）] that split the same 330 kb YAC，含有CD 3 δ和γ基因簇。 我们还 从T细胞ALL中克隆了t（11;14）（q23;q11）断裂点， SUPT 19断裂;断裂分别为端粒和着丝粒断裂 关于CD 3 YAC 至少有三种不同的易位 相关的基因。 我们正在克隆断点 在治疗相关急性髓细胞性白血病中观察到的t（3;21）中， 白血病（t-AML）和慢性粒细胞白血病急变。 21号染色体上的基因要么是同一个基因，要么是一个非常接近的基因。 与t相关的基因连锁（8;21）。 我们正在使用的 t（15;17）在急性早幼粒细胞白血病中的应用， 易位与FISH。 我们将开发新的DNA探针，通过显微切割特定的条带， 我们将使用随机引物扩增DNA， PCR法 我们将绘制这些探针相对于它们的条带或起源的图， 将它们沿着染色体排列。 我们的最终目标之一是开发可靠的方法， 或用显色探针检测这些间期重排 细胞，以便它们可以在临床实验室中用于检测 经常性的结构重排，以及常见的数字 异常 一个非常长期的目标是澄清机制 导致易位 我们的证据表明，许多易位 涉及11 q23的t-AML发生在既往接受过 依托泊苷，一种拓扑异构酶II抑制剂，提供了一个线索，如何 解决这个具有挑战性的生物学问题。

The long term objectives are to define the nature of the genetic changes that result from recurring chromosome aberrations in human leukemia. This involves cloning the breakpoints of structural chromosome rearrangements (eg translocations, inversions etc.) and identifying the genes affected by these requirements. Once the genes are cloned, their normal function and their altered function in leukemic cells can be determined. We have cloned a new gene, BCL3, on 19q13 from the t(14;19) in CLL, and are investigating its function and regulation. We have cloned the t(1;7)(p34;q34) and have identified the gene on chromosome 1 as LCK, a lymphocyte specific tyrosine kinase. Two 5' promotors of LCK are split and the 3' promoter is adjacent to T cell receptor beta. We are currently cloning the breakpoints in four translocations involving 11q23 [t(4;11), t(6;11), t(9;11) and t(11;19)] that split the same 330 kb YAC containing the CD3 delta and gamma gene cluster. We have also cloned a t(11;14)(q23;q11) breakpoint from a T cell ALL and the 11q23 break in SUPT19; the breaks are telomeric and centromeric, respectively to the CD3 YAC. There are at least three different translocation- associated genes in this chromosome band. We are cloning the breakpoint in the t(3;21) which is seen in treatment-related acute myelogenous leukemia (t-AML) and in chronic myelogenous leukemia in blast crisis. The gene on chromosome 21 is either the same gene or is a very closely linked gene to that involved in the t(8;21). We are using for the t(15;17) in acute promyelocytic leukemia that can reliably detect the translocation with FISH. We will develop new DNA probes by microdissection of specific bands of human chromosomes and we will amplify the DNA using random primers with PCR. We will map these probes relative to their band or origin and then will order them along the chromosomes. One of our ultimate goals is to develop reliable methods with either FISH or with chromogenic probes to detect these rearrangements in interphase cells so that they can be used in clinical laboratories to detect the recurring structural rearrangements, as well as the common numerical abnormalities. A very long term goal is to clarify the mechanisms leading to translocations. Our evidence that many translocation involving 11q23 in t-AML occur in patients previously treated with etoposide, a toposoimerase II inhibitor, provides a clue as to how to approach this challenging biological problem.