CHROMOSOME ABNORMALITIES AND HUMAN LEUKEMIA AND LYMPHOMA

长期目标是确定遗传变化的性质 这是由人类白血病中反复出现的染色体异常引起的， 淋巴瘤 我们将继续努力， 造血系统疾病与临床细胞遗传学的相关性 强调经常性的结构变化。 我们最近证实 急性非淋巴细胞白血病中3q 21和3q 26的重排 白血病（ANLL）与血小板增加和形态学改变有关。 巨核细胞异常。 我们发现了一种罕见的异常， t（6;9）（p23;q34）在ANLL中具有骨髓嗜碱性粒细胞增加。 急性 淋巴细胞白血病（ALL），我们发现9 p21 -22的缺失发生在 ALL伴淋巴瘤特征，可能与缺乏 甲基碘腺苷磷酸化酶。 这些数据将有助于定义新类型 急性白血病和阐明核型模式的骨髓增生异常。 更重要的是， 白血病亚型的基因涉及的断点;这些 断裂点可以精确定位基因的染色体位置， 参与了恶性转化的过程。 因此，一个主要的焦点 是染色体连接的分子分析， 易位或倒位。 在ANLL中，我们在inv（16）中显示了 （p13 q22）16 q22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，9 p中的断点分裂 α和β干扰素基因将β链移动到11 q; c-ets 通常在11 q23上的基因易位到9 p22，邻近α 干扰素基因 我们在t（8;21）中表明，c-ets的3'部分， 与No.21同源，易位在No.8的c-mos附近。 此外 我们有证据表明inv（3）（q21 q26）分裂转铁蛋白基因; 3'部分移近转铁蛋白受体。 在淋巴疾病中， 我们正在分析我们在B-CLL中识别的t（14;19），我们在B-CLL中识别的inv（14）， 首次在T-CLL中发现，另一种易位[t（8;14）（q24;q11）]在T-CLL中发现。 两个T-CLL细胞系。 在后一个易位中，我们已经表明， T细胞受体的α链易位在c-myc的3'端， 在Southern印迹分析中重排。 对于其中的几次重组 [inv（16），t（8;14）in T-CLL]我们已经在使用改变大小的限制 片段来克隆染色体断裂点。 DNA分析 连接点可以识别相关基因，并为基因组学提供见解。 基因重组的基础

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.