Dr. Kaufman's studies have focused largely on the structure and regulation of human genes that are involved in formation of blood cells and in the regulation of multigene families. Significant discoveries include the characterization of the human globin gene domain and interspersed genetic elements. His investigations have also explored mechanisms of gene regulation and expression by characterizing abnormal globin genes and thalassemia variants, and genetic conditions that affect the developmental expression of globins.
The regulation of genes expressed in hematopoietic stem cells and progenitors has been an area of particular focus in the Kaufman laboratory. In many tissues, particularly those that are hormonally responsive, controlled cellular death is used to regulate tissue mass. The innate immune system provides surveillance to eliminate tissue cells that have not successfully executed growth and death cycles.
The work of the Kaufman lab is focused on a novel receptor-ligand pair in order to understand how this process functions. CD7 is a single-domain Ig superfamily molecule expressed on human T and NK cells, as well as on cells in the early stages of T, B, and myeloid cell differentiation. CD7 is highly expressed on malignant immature T cells and is generally absent on malignant mature T cells, such as CD4+ Sezary leukemia and HTLV-1+ adult T-cell leukemia cells. Because of the lack of identification of a natural ligand and lack of a monoclonal antibody against murine CD7, the in vivo functions of CD7 have remained obscure.
Recent studies in CD7-deficient mice have provided new insights into CD7 function and demonstrated key roles for CD7 in regulating peripheral T and NK cell cytokine production and sensitivity to LPS-induced shock syndromes. Our isolation of the ligand for CD7, which we have designated K12/SECTM1, has provided new insights into possible roles for CD7 and the ligand. This ligand is a 248 amino acid protein expressed as a 27 kDa protein on the surface of the epithelial cells of mammary, ovarian, and prostate tissues and neutrophils. In addition, a ~18 kDa soluble form of the K12 protein derived from the N-terminal domain is specifically secreted by cells into the culture medium. K12/SECTM1 is overexpressed in subsets of mammary, ovarian, and prostate cancers; is induced by gamma interferon; and can activate or block activation of NK cells.
Based on these observations, the Kaufman lab is examining the biological features of K12/SECTM1 in animal and tissue culture systems. Furthermore, since CD7 is expressed on early hematopoietic progenitors, its roles in early hematopoiesis and in T and NK cell development and function are being examined.