We intend to assess the role of the BCL2 and TCL1 genes in B- and T- cell lymphocytic leukemia (CLL). Translocations involving the BCL2 gene and one of the loci of human immunoglobulins occur in only 5-7% if B-CLLs. However, high levels of BCL2 expression are observed in all B-CLLs, B-CLLs will be investigated for alterations in regulatory regions of the BCL2 gene and for over-expression of transcription factors that may up-regulate BCL2 or loss of expression of factors that down-regulate BCL2. Genes of such factors will be investigated for genetic alterations and over-expression or loss of expression in B-CLLs. We have shown that these cases for mutation of the ATM gene. Sequence analysis of these cases showed mutation in the ATM gene and loss of the normal ATM allele. Interestingly, 40% of CLL cases with ATM mutations recurred in individual heterozygous for ATM mutations, suggesting that ATM mutations may predispose to the development of B-CLL. We propose to introduce an activated BCL2 transgene into ATM-/+ mice to determine whether these mice develop an B-CLL and whether these mice lose the normal ATM allele. Recently we have discovered the TCL1 gene at 14q32.1. This gene is involved in chromosomal translocations in inversions with T cell receptor genes in post thymic types of T cell leukemias, such as pro-lymphocytic leukemia (T-PLL) and chronic T cell leukemias, such as pro-lymphocytic leukemia (T-PLL) and chronic T cell leukemia (T-CLL). We have also shown that TCL1 deregulation is an early step in the develop of T cell leukemia. We have preliminary data that TCL1, as well as BCL2, protect lymphoid cell from apoptosis. We propose to analyze the function of the Tcll protein and its role in T cell neoplasia.. We will assess the ability of TCL1 and of its homologue MTCP1 in protecting T cells from killing with corticosteroid hormones, assess the functional domains of the Tcll and Mtcp1 proteins by mutational analysis and characterize proteins interacting with Tcll, since their characterization could provide some light on the mechanisms of action of Tcll. We also propose to infect ATM knock out mice with TCL1 retroviruses to assess the cooperative role of ATM and TCL1 in T cell leukemia. T cell leukemias of uninfected AT mice will also be tested for expression of TCL1, Tcll translocations and retroviral integration at the Tcll locus. We have just discovered that the 86 Kda protein that co- immunoprecipitates with Tcll is the product of the EWS gene involved in Ewing Sarcoma. We propose to investigate the interaction between TCL1 and EWS and to determine whether alterations of EWS occur in B and T cell leukemias.
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