The curative potential of allogeneic hematopoietic cell transplantation (HCT) is in part attributable to the development of donor immune responses against alloantigens expressed on recipient leukemic cells. This 'graft versus leukemia' (GVL) effect is enhanced in the setting.of female into male transplantation, because the Y chromosome encodes a set of male-specific alloantigens that can elicit potent immune responses from female donors. These immune responses are associated with a lower relapse rate, as well as an increased risk for both acute and chronic graft versus host disease. The protein product of the gene DDX3Y is one of the most immunogenic Y chromosome-encoded targets, and elicits CD4+ T cell, CD8+ T cell, and B cell responses that are associated with GVL activity. Although the function of DDX3Y is unknown, it is required for human spermatogenesis. Transcription of the gene has been detected in a wide range of somatic tissues, as is true for its X chromosome homologue DDX3X, but its translation was previously considered to be testis-restricted. Thus, the mechanism by which DDXSY-specific immune responses could contribute to GVL has been unclear. Recent studies in our laboratory have provided the first definitive evidence that the DDX3Y protein is expressed outside the immunologic sanctuary of the testis, in both normal and malignant hematopoietic cells, including the putative leukemic stem cell that can establish human leukemia in nonobese diabetic/severe combined immune deficient (NOD/SCID) mice. These findings collectively suggest that DDX3Y plays a functional role in both normal and malignant male hematopoietic cells.
The aims of this project are to evaluate the expression and function of DDX3Y in normal and malignant male hematopoietic cells, and to characterize how DDX3Y expression is regulated by the processes of hematopoietic differentiation, activation, and cell cycle progression. The protein and mRNA expression studies will be performed on normal and malignant male hematopoietic cells, and the function will be studied using gene transfection into the HL-60 promyelocytic leukemia model. Relevance to public health: This project will study the function and expression characteristics of DDX3Y, a gene carried on the Y chromosome. Immune responses against DDX3Y contribute to the elimination of leukemia after allogeneic bone marrow or stem cell transplant. Characterization of the role played by DDX3Y in the function of normal and cancerous blood cells may lead to better treatments for leukemia.
| Warren, Edus H; Fujii, Nobuharu; Akatsuka, Yoshiki et al. (2010) Therapy of relapsed leukemia after allogeneic hematopoietic cell transplantation with T cells specific for minor histocompatibility antigens. Blood 115:3869-78 |
