In the present study, we further show the following: (i) ixazomib can effectively kill refractory/relapsed GCB and non-GCB DLBCL cells, as well as DHL cells in in vitro and in vivo models; (ii) ixazomib has low toxicity in normal PBMCs; (iii) ixazomib sensitivity correlates with immunoproteasome activity, particularly in the GCB subtype of DLBCL; (iv) ixazomib induces DNA damage and apoptosis in DLBCL cells; and (v) a CHK2 inhibitor suppresses ixazomib-induced CHK2 phosphorylation, resulting in a synergistic inhibition of cell growth and DNA damage. The gene discussed is CHEK2; the disease is diffuse large B-cell lymphoma.