Targeting primitive chronic myeloid leukemia cells by effective inhibition of a new AHI-1-BCR-ABL-JAK2 complex

Chen, M. et al. (2013) Targeting primitive chronic myeloid leukemia cells by effective inhibition of a new AHI-1-BCR-ABL-JAK2 complex. Journal of the National Cancer Institute, 105(6), pp. 405-423. (doi: 10.1093/jnci/djt006) (PMID:23446755) (PMCID:PMC3601953)

[img]
Preview
Text
78847.pdf - Published Version
Available under License Creative Commons Attribution Non-commercial.

22MB

Abstract

Background: Imatinib mesylate (IM) induces clinical remission of chronic myeloid leukemia (CML). The Abelson helper integration site 1 (AHI-1) oncoprotein interacts with BCR-ABL and Janus kinase 2 (JAK2) to mediate IM response of primitive CML cells, but the effect of the interaction complex on the response to ABL and JAK2 inhibitors is unknown. Methods: The AHI-1–BCR-ABL–JAK2 interaction complex was analyzed by mutational analysis and coimmunoprecipitation. Roles of the complex in regulation of response or resistance to ABL and JAK2 inhibitors were investigated in BCR-ABL + cells and primary CML stem/progenitor cells and in immunodeficient NSG mice. All statistical tests were two-sided. Results: The WD40-repeat domain of AHI-1 interacts with BCR-ABL, whereas the N-terminal region interacts with JAK2; loss of these interactions statistically significantly increased the IM sensitivity of CML cells. Disrupting this complex with a combination of IM and an orally bioavailable selective JAK2 inhibitor (TG101209 [TG]) statistically significantly induced death of AHI-1–overexpressing and IM-resistant cells in vitro and enhanced survival of leukemic mice, compared with single agents (combination vs TG alone: 63 vs 53 days, ratio = 0.84, 95% confidence interval [CI] = 0.6 to 1.1, P = .004; vs IM: 57 days, ratio = 0.9, 95% CI = 0.61 to 1.2, P = .003). Combination treatment also statistically significantly enhanced apoptosis of CD34+ leukemic stem/progenitor cells and eliminated their long-term leukemia-initiating activity in NSG mice. Importantly, this approach was effective against treatment-naive CML stem cells from patients who subsequently proved to be resistant to IM therapy. Conclusions: Simultaneously targeting BCR-ABL and JAK2 activities in CML stem/progenitor cells may improve outcomes in patients destined to develop IM resistance.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Holyoake, Professor Tessa and Gallipoli, Dr Paolo and Jorgensen, Dr Heather and Paul, Mr James and Stobo, Mr Jon
Authors: Chen, M., Gallipoli, P., DeGeer, D., Sloma, I., Forrest, D.L., Chan, M., Lai, D., Jorgensen, H., Ringrose, A., Wang, H.M., Lambie, K., Nakamoto, H., Saw, K.M., Turhan, A., Arlinghaus, R., Paul, J., Stobo, J., Barnett, M.J., Eaves, A., Eaves, C.J., Holyoake, T.L., and Jiang, X.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
Journal Name:Journal of the National Cancer Institute
Journal Abbr.:JNCI
Publisher:Oxford University Press
ISSN:0027-8874
ISSN (Online):1460-2105
Published Online:27 February 2013
Copyright Holders:Copyright © 2013 The Authors
First Published:First published in Journal of the National Cancer Institute 105(6):405-423
Publisher Policy:Reproduced under a Creative Commons License

University Staff: Request a correction | Enlighten Editors: Update this record