Conversion of a stem cell leukemia from a T-lymphoid to a myeloid phenotype induced by the adenosine deaminase inhibitor 2 '-deoxycoformycin (hematopoietic differentiation/S-adenosylhomocysteine/methylation inhibition/purine nucleoside toxicity/deoxycytidine deaminase)

Selective failure of lymphoid development occurs in genetic deficiency of adenosine deaminase (ADA). We examined the in vivo effects of a potent inhibitor of ADA, 2'-deoxycoformycin, which was used to treat a patient with refractory acute leukemia. Unexpectedly, within 7 days of starting treatment, the leukemic phenotype underwent com- plete conversion from T lymphoblastic to promyelocytic, with kinetics that suggested a precursor-product relationship be- tween the two cell populations. Pretreatment T lymphoblasts and posttreatment promyelocytes had the same abnormal karyotype. Upon culture in vitro, the former transformed spontaneously over several weeks into mature myeloid cells. We conclude that the leukemia arose from a multipotent stem cell capable of both lymphoid and myeloid differentiation. Ef- fects of ADA inhibition on leukemia cells during treatment in- cluded expansion of the deoxyadenosine nucleotide pool and accumulation of S-adenosylhomocysteine, a potent inhibitor of S-adenosylmethionine-dependent methylation. The influence of these changes on the leukemic phenotype is discussed in terms of (i) selective cytotoxicity to T lymphoblasts, which ac- cumulated deoxyadenosine nucleotides more efficiently than did the patient's promyelocytes during in vitro incubation with deoxycoformycin plus deoxyadenosine, and (ii) induction of an altered program of diffetentiation. In this report we describe a closely observed instance in which the phenotype of an acute leukemia changed abruptly from T lymphoid to myeloid in vivo. The phenotypic conver- sion was remarkable because it entailed not simply further maturation within a cell lineage but an apparent redirection in the program of hematopoietic differentiation. Lymphoid to myeloid conversion was related temporally to treatment with 2'-deoxycoformycin (dCF), a potent inhibitor of adeno- sine deaminase (ADA). Use of dCF to treat lymphoid malig- nancies is based on the fact that genetic deficiency of ADA causes selective absence of lymphoid tissues (1). Lympho- penia is thought to result from effects of the ADA substrates adenosine (Ado) and 2'-deoxyadenosine (dAdo), among which are expansion of the intracellular pools of the cytotox- ic nucleotide dATP, and of S-adenosylhomocysteine (AdoHcy), a potent inhibitor of S-adenosylmethionine (Ado- Met)-dependent transmethylation reactions (2). We ob- served accumulation of these compounds in the leukemia cells of our patient during treatment with dCF, and we have considered their possible influence on the leukemic pheno- type.