Seed T M, Kaspar L V
Biological and Medical Research Division, Argonne National Laboratory, Illinois 60439-4833.
Radiat Res. 1991 Oct;128(1 Suppl):S81-6.
Protracted courses of low-daily-dose gamma irradiation elicit high incidences of myeloproliferative disease, principally myeloid leukemia (ML), in beagle dogs. A four-phase preclinical sequence in the induction of ML has been described: (1) suppression, (2) recovery, (3) accommodation, and (4) preleukemic transition. Within this sequence, a critical "early"-occurring hematopoietic target cell event that promotes progression of preclinical phases I and II has been identified and characterized by an acquisition of increased radioresistance to low-LET gamma rays by granulocyte/monocyte lineage-committed progenitor cells (CFU-GM). To gain further insight into the basis of this critical event, the acquired survival response of preleukemic progenitor cells has been probed in vitro with high-LET fission neutrons. For these studies, marrow CFU-GM were isolated from chronically irradiated preleukemic dogs, as well as from nonirradiated controls, subjected to graded doses (0-300 cGy) of either JANUS fission neutrons or 60Co gamma rays, and assayed for survival by a standard cloning assay. Major observations resulting from these assays include the following. First, the acquired radioresistance of preleukemic CFU-GM to low-LET gamma rays noted previously extends to high-LET fission neutrons as well. Relative to control CFU-GM exhibited small but significant increases in radioresistance of about 10 cGy with an average D0 value of 38 (+/- 2.3) cGy for preleukemic CFU-GM, and 28 (+/- 1.3) cGy for the control levels, the CFU-GM irradiated within a marrow dose range of 10-75 cGy. Second, at higher neutron doses (150-600 cGy), fractional survival of both control and preleukemic CFU-GM declined nonexponentially, suggesting the existence of a small, radioresistant subpopulation constituting about 2% of the total marrow CFU-GM within normal nonirradiated dogs, and a 15% fraction of the progenitor cell population in preleukemic marrow (preclinical phases II-IV). The latter is most likely the result of a normally minor subpopulation gaining a growth advantage due to its inherent radioresistance and clonally expanding in the strong selective pressure of chronic marrow irradiation in vivo. We speculate that these qualitative/quantitative changes in the function of progenitor cells foster the initiation of aberrant regenerative hematopoiesis characteristic of early evolving radiation leukemogenesis.
长期低剂量的γ射线照射会在比格犬中引发高发性的骨髓增殖性疾病，主要是髓系白血病（ML）。已经描述了ML诱导过程中的一个四阶段临床前序列：（1）抑制，（2）恢复，（3）适应，以及（4）白血病前期转变。在这个序列中，一个关键的“早期”发生的造血靶细胞事件已被识别并表征，该事件促进临床前I期和II期的进展，其特征是粒细胞/单核细胞系定向祖细胞（CFU-GM）对低LETγ射线的放射抗性增加。为了进一步深入了解这一关键事件的基础，已在体外使用高LET裂变中子探测白血病前期祖细胞获得的存活反应。对于这些研究，从长期照射的白血病前期犬以及未照射的对照犬中分离出骨髓CFU-GM，使其接受不同剂量（0-300 cGy）的JANUS裂变中子或60Coγ射线照射，并通过标准克隆试验测定其存活率。这些试验得出的主要观察结果如下。首先，先前观察到的白血病前期CFU-GM对低LETγ射线获得的放射抗性也扩展到了高LET裂变中子。相对于对照CFU-GM，白血病前期CFU-GM的放射抗性有小幅但显著的增加，约为10 cGy，白血病前期CFU-GM的平均D0值为38（±2.3）cGy，对照水平为28（±1.3）cGy，在10-75 cGy的骨髓剂量范围内照射的CFU-GM。其次，在较高的中子剂量（150-600 cGy）下，对照和白血病前期CFU-GM的分数存活率均呈非指数下降，这表明在正常未照射的犬中存在一个小的放射抗性亚群，约占总骨髓CFU-GM的2%，在白血病前期骨髓（临床前II-IV期）中占祖细胞群体的15%。后者很可能是由于一个通常较小的亚群因其固有的放射抗性获得生长优势，并在体内慢性骨髓照射的强大选择压力下进行克隆性扩增的结果。我们推测，祖细胞功能的这些定性/定量变化促进了早期辐射白血病发生特征性的异常再生造血的启动。
