Mechanisms of resistance to high and low linear energy transfer radiation in myeloid leukemia cells

Low linear energy transfer (LET) ionizing radiation (IR) is an important form of therapy for acute leukemias administered externally or as radioimmunotherapy. IR is also a potential source of DNA damage. High LET IR produces structurally different forms of DNA damage and has emerged as potential treatment of metastatic and hematopoietic malignancies. Therefore, understanding mechanisms of resistance is valuable. We created stable myeloid leukemia HL60 cell clones radioresistant to either gamma-rays or alpha-particles to understand possible mechanisms in radioresistance. Cross-resistance to each type of IR was observed, but resistance to clustered, complex alpha-particle damage was substantially lower than to equivalent doses of gamma-rays. The resistant phenotype was driven by changes in: apoptosis; late G(2)/M checkpoint accumulation that was indicative of increased genomic instability; stronger dependence on homology-directed repair; and more robust repair of DNA double-strand breaks and sublethal-type damage induced by gamma-rays, but not by alpha-particles. The more potent cytotoxicity of alpha-particles warrants their continued investigation as therapies for leukemia and other cancers. (Blood. 2012; 120(10):2087-2097)