CONVERSION OF A STEM-CELL LEUKEMIA FROM A LYMPHOID-T TO A MYELOID PHENOTYPE INDUCED BY THE ADENOSINE-DEAMINASE INHIBITOR 2'-DEOXYCOFORMYCIN
CONVERSION OF A STEM-CELL LEUKEMIA FROM A LYMPHOID-T TO A MYELOID PHENOTYPE INDUCED BY THE ADENOSINE-DEAMINASE INHIBITOR 2'-DEOXYCOFORMYCIN
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DOI：
10.1073/pnas.81.1.253
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发表时间：
1984-01-01
期刊：
影响因子：
--
通讯作者：
HAYNES, BF
中科院分区：
文献类型：
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作者：
HERSHFIELD, MS;KURTZBERG, J;HAYNES, BF
选择性淋巴细胞发育失败发生在腺苷脱氨酶（ADA）的遗传缺陷。研究了用于治疗难治性急性白血病患者的一种有效的ADA抑制剂，2 " -脱氧克福霉素的体内作用。出乎意料的是，在开始治疗的7天内，白血病表型从T淋巴细胞完全转化为早幼粒细胞，动力学表明两种细胞群之间存在前体产物关系。治疗前的T淋巴细胞与治疗后的早幼粒细胞具有相同的异常核型。体外培养后，前者在几周内自然转化为成熟的髓细胞。白血病起源于一种多能干细胞，能同时分化淋巴细胞和髓细胞。在治疗期间，ADA抑制对白血病细胞的影响包括脱氧腺苷核苷酸库的扩大和s -腺苷型同型半胱氨酸的积累，s -腺苷型蛋氨酸依赖甲基化的有效抑制剂。这些变化对白血病表型的影响是根据对T淋巴细胞的选择性细胞毒性来讨论的，T淋巴细胞在体外培养期间比患者的早幼粒细胞更有效地积累脱氧腺苷核苷酸，并诱导分化程序的改变。
Selective failure of lymphoid development occurs in genetic deficiency of adenosine deaminase (ADA). The in vivo effects of a potent inhibitor of ADA, 2''-deoxycoformycin, which was used to treat a patient with refractory acute leukemia, were examined. 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 2 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. 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 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 induction of an altered program of differentiation.