UC Irvine

The product of the Ph chromosome, the BCR-ABL1 tyrosine kinase activates diverse signaling pathways in leukemic cells from patients with chronic myeloid leukemia (CML) and Ph(+) B-cell acute lymphoblastic leukemia (B-ALL). Previous studies showed that nuclear factor κB (NF-κB) is activated in BCR-ABL1-expressing cells, but the mechanism of activation and importance of NF-κB to the pathogenesis of BCR-ABL1-positive myeloid and lymphoid leukemias are unknown. Coexpression of BCR-ABL1 and a superrepressor mutant of inhibitory NF-κB α (IκBαSR) blocked nuclear p65/RelA expression and inhibited the proliferation of Ba/F3 cells and primary BCR-ABL1-transformed B lymphoblasts without affecting cell survival. In retroviral mouse models of CML and B-ALL, coexpression of IκBαSR attenuated leukemogenesis, prolonged survival, and reduced myeloid leukemic stem cells. Coexpression of dominant-negative mutants of IκB kinase α (IKKα)/IKK1 or IKKβ/IKK2 also inhibited lymphoid and myeloid leukemogenesis by BCR-ABL1. Blockade of NF-κB decreased expression of the NF-κB targets c-MYC and BCL-X and increased the sensitivity of BCR-ABL1-transformed lymphoblasts to ABL1 kinase inhibitors. These results demonstrate that NF-κB is activated through the canonical IKK pathway and plays distinct roles in the pathogenesis of myeloid and lymphoid leukemias induced by BCR-ABL1, validating NF-κB and IKKs as targets for therapy of Ph(+) leukemias.