PROGRESSION OF T CELL LYMPHOMA LINES TO IL2 INDEPENDENCE

Thomas Jefferson University, Philadelphia PA

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Abstract

DESCRIPTION: (adapted from the investigator's abstract) The Gfi-1 proto-oncogene is activated by provirus integration in T cell lymphoma lines selected for IL-2 independence in culture and in primary retrovirus-induced thymomas and collaborates with c-myc and pim-1 in oncogenesis. Gfi-1 encodes a zinc finger protein with six C2H2 type, C-terminal zinc finger motifs. The investigator s recent studies have shown that Gfi-1 is a 55 kD nuclear protein that binds DNA in a sequence specific manner and functions as a position and orientation independent active transcriptional repressor. Repressor activity depends on a novel twenty amino acid N-terminal repressor domain, coincident with a nuclear localization motif. The sequence of the Gfi-1 repressor domain is related to the sequence of the repressor domain of Gfi-1B, a Gfi-1 related protein, and to sequences at the N-termini of the insulinoma-associated protein, IA-1, the homeobox protein Gsh-1 and the vertebrate members of the Snail-Slug protein family. Among the genes repressed by Gfi-1 are p21WAF1, encoding a cyclin dependent kinase inhibitor, and Bax, an inducer of apoptosis, both of which are upregulatd by the tumor suppressor gene p53. Gfi-1 mediated repression is associated with inhibition of cell death and abrogation of the G1 checkpoint induced by IL-2 withdrawal in T cells. Induction of Gfi-1 may therefore contribute to T-cell activation and tumor progression by promoting cell cycle progression and by increasing cell viability. The Gfi-1 related protein Gfi-1B is expressed transiently during primitive embryonic hematopoiesis. In adult animals it is expressed in the less differentiated B and myeloid cells. Gfi-1B also represses expression of p21 and inhibits myeloid cell differentiation. He now proposes to examine the role of Gfi-1 and Gfi-1B in cell cycle progression, apoptosis, hematopoietic cell differentiation and oncogenesis, and to characterize functionally the Snail-Gfi-1 (SNAG) repressor domain. The long term objective of this project is to use Gfi-1 and Gfi-1B as probes to explore the biology of the hematopoietic system and the pathobiology of neoplasia with emphasis on cell cycle progression differentiation and apoptosis.