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 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.