CHROMOSOME ABNORMALITIES AND HUMAN LEUKEMIA AND LYMPHOMA

长期目标是定义基因变化的性质 这是由人类白血病反复发生的染色体异常引起的。 这涉及到克隆结构染色体的断裂点 重排(如移位、倒置等)并标识 受这些要求影响的基因。一旦这些基因被克隆，他们的 白血病细胞的正常功能及其改变的功能可以 下定决心。 我们在19q13从CLL的t(14；19)克隆了一个新的基因bcl3，并且 正在研究其功能和调控。我们已经克隆了 T(1；7)(p34；q34)，并鉴定1号染色体上的基因为LCK，a 淋巴细胞特异性酪氨酸激酶。LCK的两个5‘端启动子分裂 3‘端启动子与T细胞受体β相邻。 我们目前正在克隆四个易位中的断点，包括 分割相同330的11q23[t(4；11)、t(6；11)、t(9；11)和t(11；19)] Kb YAC含有CD3 Delta和Gamma基因簇。我们还有 从T细胞ALL和11q23克隆了t(11；14)(q23；q11)断裂点 SUPT19中的中断；中断分别是端粒和着丝粒 给CD3 YAC。至少有三种不同的易位- 这条染色体带中的相关基因。我们正在克隆断点 在t(3；21)中，可见与治疗相关的急性髓系白血病 白血病(t-AML)和慢性粒细胞白血病急变期。 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 该基因与t(8；21)所涉及的基因连锁。我们使用的是 T(15；17)在急性早幼粒细胞白血病中可以可靠地检测到 和鱼一起移位。 我们将通过显微解剖特定的条带来开发新的DNA探针 我们将使用随机引物扩增DNA， 聚合酶链式反应。我们将根据它们的波段或来源来映射这些探测器，然后 将沿着染色体对它们进行排序。 我们的最终目标之一是开发两种鱼的可靠方法 或使用显色探针来检测间期的这些重排 细胞，以便它们可以在临床实验室中用于检测 重复的结构重新安排，以及共同的数字 异常现象。一个非常长期的目标是澄清这些机制 导致移位。我们的证据表明许多移位 T-AML中涉及11q23的患者以前接受过 依托泊苷是一种拓扑异构酶II的抑制剂，它为如何 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.