As a major loss of C-NHEJ function, such as the deficiency of DNA-PKcs, Ku70, Ku80, XRCC4, DNA ligase 4, or Artemis, can lead to a number of intrinsic health issues such as growth defects, immunodeficiency, or inherent chromosomal instabilities,13, 15 the Aplf–/– mouse, with moderate impairment of the C-NHEJ pathway and specific sensitivities to genotoxic treatments, becomes a good model to address therapy-induced malignant evolution. The gene discussed is XRCC4; the disease is Immunodeficiency.