Drug Resistance in T-Cell Acute Lymphoblastic Leukemia Human T- and B-Lymphoblasts as a Model for the Development Determinants of Deoxyadenosine Toxicity in Hybrids between

Cultured human T-lymphoblastoid cell lines are more sensitive than B-cell lines to 2'-deoxyadenosine in the presence of 2'deoxycoformycin, a potent inhibitor of adenosine deaminase. This difference is related to the greater efficiency with which Tlymphoblasts accumulate cytotoxic levels of dATP derived from the adenosine deaminase substrate 2'-deoxyadenosine (dAdo). Previous work has shown that differences in dATP accumulation by cultured Tand B-lymphoblastoid cell lines cannot be ex plained by large differences in the levels of dAdo-phosphorylating or dAdo nucleotide (dAXP)-degrading activities in cytoplasmic extracts of these cells, although it has been proposed that intact B-cell lines may catabolize intracellular dAXP more rapidly than do T-cell lines. To further examine the determinants of dAdo sensitivity in Tand B-lymphoblasts, we have studied dAdo and dAXP metabolism in the human Tand B-cell lines CEM and WlL2 and in hybrids generated by fusion of these cell lines. The hybrid nature of the fusion products was established by nutri tional studies and by analyses of cellular surface antigens, DNA content, and enzymatic activities. We found that WI-L2 x CEM hybrids and another T x B hybrid derived from fusion of the SB human B-cell line with CEM were 30to 40-fold less sensitive to dAdo and about 10-fold less sensitive to the dAdo analogue 9/î-D-arabinofuranosyladenine than was CEM, or about as resist ant as were their B-cell parental lines. Our studies confirm that CEM avidly accumulates dAXP from dAdo but does not ca tabolize intracellular dAXP. In contrast, WI-L2, SB, and WI-L2 x CEM and SB x CEM hybrids rapidly degraded intracellular dAXP, which limited their ability to undergo dAXP pool expansion. Expression of dAXP catabolic activity in T x B hybrids behaved as a dominant mechanism, conferring resistance to dAdoand dAdo-related nucleosides to T x B hybrids. It has been postu lated that cell fusion may play a role in the progression of tumors and contribute to diversity among the cells that compose clonal tumors. We have speculated that fusion of a malignant T-lymphoblast with an activated B-cell might be a mechanism for the evolution of drug resistance in acute T-cell leukemia.