Bcr-Abl activates AURKA and AURKB in chronic myeloid leukemia cells via AKT signaling.
This study explored molecular mechanisms by which Bcr-Abl induced expression of Aurora kinase A and B (AURKA and AURKB) in chronic myeloid leukemia cells. Lentiviral transduction of Bcr-Abl into either Ba/F3 or CD34(+) hematopoietic stem/progenitor cells potently increased levels of AURKA and AURKB in association with phosphorylation of AKT and stimulated their proliferation. Bcr-Abl-mediated expression of AURKA and AURKB were decreased in CD34(+) HSPCs when AKT was inactivated by an shRNA against AKT, suggesting that Bcr-Abl induced expression of AURKA and AURKB via AKT signaling. MLN8237, an inhibitor of AURKA, significantly inhibited the proliferation of freshly isolated CD34(+) CML cells in a dose-dependent manner as measured by colony forming assay. Importantly, inhibition of AURKA in CD34(+) leukemia cells freshly isolated from individuals with blast crisis of CML with Bcr-Abl T315I mutant (n = 2) by MLN8237 significantly impaired the engraftment of these cells in severely immunocompromised mice and decreased the weight of spleens. Taken together, Bcr-Abl induces expression of AURKA and AURKB at least in part via AKT. Inhibition of AURKA could be useful to overcome imatinib-resistance mediated by Bcr-Abl mutants.
Department of Hematology and Respiratory Medicine, Kochi University, Nankoku, Kochi, Japan; Department of Immunology, Kochi Medical School, Kochi University, Kochi University, Nankoku, Kochi, Japan.
Jing
J
Yang
Takayuki
T
Ikezoe
Chie
C
Nishioka
Keiko
K
Udaka
Akihito
A
Yokoyama
D000818:Animals; D064096:Aurora Kinase A / Q000378:metabolism*; D064107:Aurora Kinase B / Q000378:metabolism*; D001381:Azepines / Q000494:pharmacology; D049109:Cell Proliferation / Q000187:drug effects; D004789:Enzyme Activation; D016044:Fusion Proteins, bcr-abl / Q000235:genetics / Q000502:physiology*; D006801:Humans; D016086:Lentivirus / Q000235:genetics; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000201:enzymology*; D051379:Mice; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology*; D011743:Pyrimidines / Q000494:pharmacology; D015398:Signal Transduction / Q000502:physiology*
D001381:Azepines; C550258:MLN 8237; D011743:Pyrimidines; D016044:Fusion Proteins, bcr-abl; C576917:AURKA protein, human; C576921:AURKB protein, human; D064096:Aurora Kinase A; D064107:Aurora Kinase B; D051057:Proto-Oncogene Proteins c-akt
AKT; AURKA; AURKB; Bcr-Abl