CHROMOSOME ABNORMALITIES AND HUMAN LEUKEMIA AND LYMPHOMA

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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.