The prevailing view of natural history of lymphomagenesis in immunodeficiency disorders invokes a sequence of causally related immunological and cellular genetic events. Thus, immunodeficiency sets in motion an abnormal polyclonal proliferation of lymphoid cells initiated by intrinsic (chronic antigenic stimulation, defective immune surveillance), or extrinsic (infection by oncogenic herpes viruses) factors. Monoclonal malignant proliferation is viewed as being promoted by activation of relevant oncogene(s) which, as in the case of burkitt's lymphoma, is mediated by chromosome rearrangment. Normal, pre-neoplastic, and neoplastic proliferation of lymphoid cells in general is associated with genomic instability which manifests as chromosome breakage and/or emergence of clones with specific chromosome rearrangements. This instability is enhanced in the constitutional cells of several genetically determined immunodeficiency disorders (GDID) correlating with their increased predisposition to development of lymphoid malignancies. The so-called acquired immunodeficiency syndrome (AIDS) comprises a group of clinical disorders which have recently emerged as an """"""""epidemic"""""""" among sub-groups of male homosexuals and other populations. They are characterized by opportunistic infections, a profound disturbance in the T-cell system, lymphadenopathy, and predisposition to lymphoma, Kaposi's sarcoma, and other malignancies. While the existence of an infectious, possibly viral, etiologic agent for AIDS remains a valid hypothesis, the natural history of lymphoid proliferation and the origin of lymphoma in these disorders find parallel in GDID and immunodepression of post-transplantation patients. Hence, AIDS offers unusual opportunities for the study of chromosome changes in relation to lymphoid proliferation and origin of lymphoma. We propose to perform the following studies on AIDS patients: (1) investigate chromosome breakage and possible emergence of clonal chromosome changes in sub-populations of T-cells (helper, suppressor, natural killer) and B-cells. (2) Analyze chromosome breakage and emergence of clonal chromosome changes in lymphadenopathy representing different stages in the development of lymphoma. (3) Analyze clonal chromosome changes in AIDS lymphoma and compare them with changes seen in lymphoma developing in GDID patients and in normals. (4) Evaluate the status of Epstein-Barr virus in tumor cells by assaying for viral nuclear antigen and viral genome copy numbers. (5) Study the patterns of transposition of the cellular oncogenes, c-myc, c-myb, and c-ras in lymphoma cells. Methods employed in these studies will be those of immunology (lymphocyte subset purification by gradients and panning methods followed by stimulation with mitogens and interleukins), cytogenetics (chromosome breakage and banding analysis), and molecular genetics (DNA hybridization, single copy gene mapping).

Project Start
1984-02-01
Project End
1989-01-31
Budget Start
1986-02-01
Budget End
1987-01-31
Support Year
3
Fiscal Year
1986
Total Cost
Indirect Cost
Name
Sloan-Kettering Institute for Cancer Research
Department
Type
DUNS #
064931884
City
New York
State
NY
Country
United States
Zip Code
10065
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