IKK-dependent activation of NF-κB contributes to myeloid and lymphoid leukemogenesis by BCR-ABL1.
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.
Molecular Oncology Research Institute, Tufts Medical Center, Boston, MA;
Mo-Ying
MY
Hsieh
Richard A
RA
Van Etten
D000818:Animals; D015139:Blotting, Southern; D015153:Blotting, Western; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism*; D004789:Enzyme Activation / Q000502:physiology; D005455:Fluorescent Antibody Technique; D016044:Fusion Proteins, bcr-abl / Q000235:genetics; D051550:I-kappa B Kinase / Q000378:metabolism*; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018613:Microscopy, Confocal; D016328:NF-kappa B / Q000378:metabolism*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics / Q000378:metabolism*; D014161:Transduction, Genetic
D016328:NF-kappa B; D016044:Fusion Proteins, bcr-abl; D051550:I-kappa B Kinase; C496562:Ikbkb protein, mouse