A LYMPHOHEMATOPOIETIC STEM CELL MODEL FOR ADENOSINEDEAMINASE (ADA) DEFICIENCY: 105

Abstract

In two reported instances treatment with the ADA inhibitor deoxycoformycin (dCF) has resulted in abrupt conversion from a T lymphoblastold to a promyelocytic phenotype in patients presumed to have acute stem cell leukemia. We have established the DU.528 cell line from leukemic cells of one such patient, in whom we had documented biochemical consequences of ADA inhibition (dATP and S-adenosylhomocysteine accumulation) during dCF treatment (Hershfield et al, PNAS 81:253, 1984). In culture and as a xenograft in nude mice, DU.528 displays the ability to undergo differentiation into lymphoid, myeloid, erythroid and megakaryocytic lineages, properties of a pluripotent stem cell. In various experiments dCF + 2-20 uM Ado and dAdo induce 20-80% of T lymphoblastoid DU.528 cells to acquire myeloid surface antigens and functional characteristics, and 20-60% to synthesize hemoglobin. Treatment of nude mice bearing DU.528 xenografts with dCF induces T-lymphoblastoid to promyelocytic conversion, similar to the transformation observed in vivo. We hypothesize that the pluripotent lymphohematopoletic stem cell may be a target for effects of ADA substrates in genetic ADA deficiency, and that interference with lymphoid differentiation rather than lymphocyte viability may be responsible for the selective absence of lymphoid lineages in ADA deficiency. The DU.528 cell line provides a unique model for examing the biochemical basis for effects of purines on lymphohematopoletic differentiation.