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- Title
Targeting Primitive Chronic Myeloid Leukemia Cells by Effective Inhibition of a New AHI-1-BCR-ABL-JAK2 Complex.
- Authors
Min Chen; Gallipoli, Paolo; DeGeer, Donna; Sloma, Ivan; Forrest, Donna L.; Chan, Matthew; Lai, Damian; Jorgensen, Heather; Ringrose, Ashley; Hui Mi Wang; Lambie, Karen; Nakamoto, Helen; Kyi Min Saw; Turhan, Ali; Arlinghaus, Ralph; Paul, James; Stobo, Jon; Barnett, Michael J.; Eaves, Allen; Eaves, Connie J.
- Abstract
Background: Imatinib mesylate (IM) induces clinical remission of chronic myeloid leukemia (CML).The Abelson helper integra-tion site 1 (AHI-1 ) oncoprotein interacts with BCR-ABL and Janus kinase 2 (JAK2) to mediate IM response of primi-tive 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 com-plex 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 leu-kemic mice, compared with single agents (combination vsTG 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.
- Subjects
TREATMENT of chronic myeloid leukemia; CANCER cells; TARGETED drug delivery; PROTEIN-protein interactions; ENZYME inhibitors; PROGENITOR cells
- Publication
JNCI: Journal of the National Cancer Institute, 2013, Vol 105, Issue 6, p405
- ISSN
0027-8874
- Publication type
Article
- DOI
10.1093/jnci/djt006