Here we demonstrated that 1) a substantial fraction of DLBCLs display constitutive expression of the DNA damage marker γH2AX, which was associated with poor prognosis following conventional R-CHOP/CHOP-like chemoimmunotherapy, 2) that c-MYC expression, γH2AX and DDR activation were significantly associated, confirming the intimate relationship between oncogene–induced genomic instability and DDR activation in DLBCL, and 3) that DLBCL cell lines and primary cells exhibiting constitutive activation of the DDR pathway are very sensitive to the inhibition of checkpoint kinases. This evidence concerns the gene DDIT3 and diffuse large B-cell lymphoma.