Probing Altered Hematopoietic Progenitor Cells of Preleukemic Dogs with JANUS Fission Neutrons

Abstract

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.