Focus: Targeting Primitive Chronic Myeloid Leukemia Cells by Effective Inhibition of a New AHI-1-BCR-ABL-JAK2 Complex

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.

Source: Targeting Primitive Chronic Myeloid Leukemia Cells by Effective Inhibition of a New AHI-1-BCR-ABL-JAK2 Complex. Chen M, Gallipoli P, Degeer D, Sloma I, Forrest DL, Chan M, Lai D, Jorgensen H, Ringrose A, Wang HM, Lambie K, Nakamoto H, Saw KM, Turhan A, Arlinghaus R, Paul J, Stobo J, Barnett MJ, Eaves A, Eaves CJ, Holyoake TL, Jiang X (xjiang@bccrc.ca). J Natl Cancer Inst. 2013 Feb 27.

Free paper available at:

http://jnci.oxfordjournals.org/content/early/2013/02/26/jnci.djt006.full.pdf+html