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)

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

22MB

Abstract

<p>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.</p> <p>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.</p> <p>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.</p> <p>Conclusions: Simultaneously targeting BCR-ABL and JAK2 activities in CML stem/progenitor cells may improve outcomes in patients destined to develop IM resistance.</p>

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Paul, Mr James and Stobo, Mr Jon and Holyoake, Professor Tessa and Gallipoli, Dr Paolo and Jorgensen, Dr Heather
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

Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
498551Key survival pathways in chronic myeloid leukaemic (CML) stem cells and novel approaches to their eradicationTessa HolyoakeCancer Research UK (CAN-RES-UK)C11074/A11008RI CANCER SCIENCES
474621CRUK Clinical Trials Unit Glasgow - Quinquennial reviewJames PaulCancer Research UK (CAN-RES-UK)C973/A9894MVLS ICS - CLINICAL TRIALS UN. GARTNAVEL
474622CRUK Clinical Trials Unit Glasgow - Quinquennial reviewJames PaulCancer Research UK (CAN-RES-UK)C973/A9894MVLS ICS - CLINICAL TRIALS UN. GARTNAVEL
474623CRUK Clinical Trials Unit Glasgow - Quinquennial reviewJames PaulCancer Research UK (CAN-RES-UK)C973/A9894MVLS ICS - CLINICAL TRIALS UN. GARTNAVEL