Hershfield M S, Kurtzberg J, Harden E, Moore J O, Whang-Peng J, Haynes B F
Proc Natl Acad Sci U S A. 1984 Jan;81(1):253-7. doi: 10.1073/pnas.81.1.253.
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 complete conversion from T lymphoblastic to promyelocytic, with kinetics that suggested a precursor-product relationship between 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. Effects of ADA inhibition on leukemia cells during treatment included 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 accumulated 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 differentiation.
腺苷脱氨酶（ADA）基因缺陷会导致淋巴细胞发育的选择性失败。我们研究了一种强效ADA抑制剂2'-脱氧助间型霉素的体内效应，该抑制剂曾用于治疗一名难治性急性白血病患者。出乎意料的是，在开始治疗的7天内，白血病表型从T淋巴母细胞完全转变为早幼粒细胞，其动力学表明这两种细胞群体之间存在前体-产物关系。治疗前的T淋巴母细胞和治疗后的早幼粒细胞具有相同的异常核型。在体外培养时，前者在数周内自发转化为成熟髓细胞。我们得出结论，白血病起源于一种能够进行淋巴样和髓样分化的多能干细胞。治疗期间ADA抑制对白血病细胞的影响包括脱氧腺苷核苷酸池的扩大和S-腺苷同型半胱氨酸的积累，S-腺苷同型半胱氨酸是一种强效的S-腺苷甲硫氨酸依赖性甲基化抑制剂。这些变化对白血病表型的影响从以下两方面进行了讨论：（i）对T淋巴母细胞的选择性细胞毒性，在与脱氧助间型霉素加脱氧腺苷进行体外孵育时，T淋巴母细胞比患者的早幼粒细胞更有效地积累脱氧腺苷核苷酸；（ii）诱导分化程序改变。
