CHROMOSOME ABNORMALITIES AND HUMAN LEUKEMIA AND LYMPHOMA

长期目标是定义基因变化的性质 这是由人类白血病和反复出现的染色体异常引起的 淋巴瘤。我们将继续努力寻找新的 血液病伴发AN的临床-细胞遗传学相关性 强调经常性的结构变化。我们最近确认了 急性非淋巴细胞中同时涉及3q21和3q26的重排 白血病(ANLL)与血小板和形态的增加有关 巨核细胞异常。我们发现了一种罕见的反常现象， T(6；9)(p23；q34)使骨髓嗜碱性粒细胞增多。在急性期 淋巴细胞白血病(ALL)我们发现9p21-22缺失发生在 都有淋巴瘤的特征，可能与一种缺陷有关 亚甲基腺苷磷酸化酶。这些数据将有助于定义新类型 并阐明骨髓增生异常的核型模式。 更重要的是生物特征的相关性 白血病亚群与涉及断点的基因有关；这些 断点可以精确定位关键基因的染色体位置 参与恶变的过程。因此，一个主要的焦点是 是与染色体连接相关的分子分析 移位或倒置。在ANLL中，我们已经在Inv(16)中显示 (P13q22)16q22中的断裂点发生在金属硫蛋白内 基因簇。类似地，在t(9；11)(p22；q23)中，9P中的中断分裂 α和β干扰素基因将β链移至11q；c-ETS 基因通常在11q23上易位到9p22，与 干扰素基因。我们在t(8；21)中证明了c-ETS的3‘部分， 与21号同源的基因被移位到8号的c-mos附近。 我们有证据证明inv(3)(Q21q26)分裂转铁蛋白基因； 3‘端部分靠近转铁蛋白受体。在淋巴系统疾病中， 我们正在分析我们在B-CLL中确定的t(14；19)，即我们 首次在T-CLL中发现，另一位易位[t(8；14)(q24；q11)] 两个T-CLL细胞系。在后一种易位中，我们已经证明了 T细胞受体的阿尔法链是c-myc的3‘转位，这是 经Southern印迹分析重排。对于其中的几个重新安排 [T-CLL中的Inv(16)，t(8；14)]我们已经在使用更改的大小限制 克隆染色体断裂点的片段。病毒的DNA分析 连接可能识别涉及的基因，并为 重排的遗传基础。

The long term objectives are to define the nature of the genetic changes that result from recurring chromosome abnormalities in human leukemia and lymphoma. We will continue our efforts to identify new clinical-cytogenetic correlations in hematopoietic diseases with an emphasis on recurring structural alterations. We have recently confirmed that rearrangements involving both 3q21 and 3q26 in acute nonlymphocytic leukemia (ANLL) are associated with increased platelets and morphologic abnormalities of megakaryocytes. We showed that a rare abnormality, t(6;9)(p23;q34) in ANLL has increased basophils in bone marrow. In acute lymphoblastic leukemia (ALL) we showed that a deletion of 9p21-22 occurs in ALL with lymphomatous features and that it may be related to a deficiency of methylioadensine phosphorylase. These data will help define new types of acute leukemia and clarify karyotypic pattern in the myelodysplasias. Of greater significance is the correlation of the biological features of leukemia subsets to the genes involved in the breakpoints; these breakpoints pinpoint the chromosome location of genes that are critically involved in the process of malignant transformation. Thus, a major focus is the molecular analysis of the chromosome junctions associated with translocations or inversions. In ANLL, we have shown in the inv(16) (p13q22) that the breakpoint in 16q22 occurs within the metallothionein gene cluster. Similarly, in the t(9;11) (p22;q23) the break in 9p splits the alpha and beta interferon genes moving the beta chain to 11q; the c-ets gene normally on 11q23 is translocated to 9p22, adjacent to the alpha interferon gene. We showed in the t(8;21) that the 3' part of c-ets, homologous to No. 21, is translocated near to c-mos on No. 8. In addition we have evidence that the inv(3) (q21q26) splits the transferrin gene; the 3' part is moved close to the transferrin receptor. In lymphoid disorders, we are analyzing the t(14;19) we identified in B-CLL, the inv(14) which we first identified in T-CLL, and another translocation [t(8;14)(q24;q11)] in two T-CLL cell lines. In the latter translocation we have shown that the alpha chain for the T cell receptor is translocated 3' of c-myc which is rearranged on Southern blot analysis. For several of these rearrangements [inv(16), t(8;14) in T-CLL] we are already using altered sized restriction fragments to clone the chromosome breakpoint. DNA analysis of the junctions may identify the genes involved, and provide insights to the genetic basis for rearrangement.