Radiation resistance of primary clonogenic blasts from children with acute lymphoblastic leukemia.

Abstract

Detailed comparative analyses of the radiation sensitivity of primary clonogenic blasts from children with acute lymphoblastic leukemia (ALL) were performed to achieve a better understanding of clinical radiation resistance in ALL. The radiation sensitivity of primary clonogenic blasts from 74 children with newly diagnosed acute lymphoblastic leukemia (ALL) was analyzed using leukemic progenitor cell (LPC) assays. Primary bone marrow blasts from all 74 patients were exposed to ionizing radiation and subsequently assayed for LPC-derived blast colony formation. Radiation survival curves of primary clonogenic blasts (i.e., LPC) were constructed for each of the newly diagnosed patients using computer programs for the single-hit multitarget as well as the linear quadratic models of cell survival. A marked interpatient variation in intrinsic radiation sensitivity was observed between LPC populations. The SF2 values ranged from 0.01 to 1.00 (median: 0.36; mean +/- SE = 0.40 +/- 0.03), and the alpha values ranged from 0.00 Gy-1 to 3.27 Gy-1 (median: 0.280 Gy-1; mean +/- SE = 0.43 +/- 0.09 Gy-1). Patients were divided into groups according to their sex, age, WBC at diagnosis, cell cycle distribution of leukemic blasts, and immunophenotype. Only immunophenotype provided a significant correlation with the intrinsic radiation sensitivity of LPC. Patients with B-lineage ALL had higher SF2 (0.47 +/- 0.04 vs. 0.31 +/- 0.05, p < 0.05) and smaller alpha values (0.43 +/- 0.09 Gy-1 vs. 0.65 +/- 0.10 Gy-1, p < 0.05) than T-lineage ALL patients, consistent with greater intrinsic radiation resistance at the level of LPC. Notably, 43% of B-lineage ALL cases, but only 27% of T-lineage ALL cases had LPC with SF2 > or = 0.5. Similarly, 66% of B-lineage ALL cases, but only 37% of T-lineage ALL cases had LPC with alpha values < or = 0.4 Gy-1. Combining the two indicators of radiation resistance, we found that only 34% of the B-lineage ALL patients had none of the two parameters in the respective critical regions (alpha < or = 0.4 Gy-1; SF2 > or = 0.5), while 63% of the T-lineage patients had none (p < 0.05). In multivariate analyses, the immunophenotypic B-lineage affiliation was the only significant predictor of radiation resistance at the level of LPC. Whether alone or in combination, none of the other variables examined, including sex, age, WBC, in vitro plating efficiency, S-phase index, and proliferation index were significantly correlated with the radiation sensitivity or resistance of LPC. These results offer unprecedented evidence for an association between composite immunophenotype (viz., B-lineage ALL vs T-lineage ALL) and radiation resistance that may form a basis for modifying radiation conditioning regimens.