In the present study, we elucidated the mechanism by which NF-κB is activated in CML and TKI resistance, implicating two important and novel findings: (1) the non-ATPase proteasome subunits, PSMD1 and PSMD3, are upregulated during CML disease progression (Fig. 3) and promote NF-κB protein expression in CML (Fig. 7), and (2) STAT3 further activates NF-κB in scenarios of TKI resistance (Fig. 8). This evidence concerns the gene NFKB1 and chronic myelogenous leukemia, BCR-ABL1 positive.