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A novel oncogene AHI-1 interacts with BCR-ABL and JAK2 and mediates cellular resistance to tyrosine kinase inhibitors in CML

University of British Columbia

Chronic myeloid leukemia is a myeloproliferative disorder characterized by the presence of the Philadelphia chromosome, encoding a unique fusion gene BCR-ABL. The current first line treatment for patients diagnosed with CML involves administration of the ABL kinase inhibitor imatinib mesylate (IM). However, early relapses and acquired drug resistance remain a current impediment to successful treatment for many patients. This suggests the necessity for alternate treatment options which may include combination therapy targeting multiple vital proteins involved in the malignancy of the leukemia. AHI-1 (Abelson helper integration site 1) is a recently discovered oncogene that is highly deregulated in murine lymphomas and leukemias. AHI-1 displays a significant pattern of overexpression in a Philadelphia chromosome positive cell line K562 cells. To investigate AHI-1’s involvement in CML, AHI-1 was either stably overexpressed or suppressed in K562 cells. Interestingly, an increase in cellular proliferation and colony formation and a decrease in apoptosis were observed in the presence of IM when AHI-1 was overexpressed, while suppression of AHI-1 had the opposite effects. Phosphorylation and total protein expression levels of several proteins known to be involved in BCR-ABL signalling were quantified. Interestingly, elevated phosphorylation and total gene/protein expression levels of several of these proteins were observed when AHI-1 was overexpresessed, in particular NF-κB and JAK2/STAT5 displayed increased expression. Due to the strong effects AHI-1 had on the JAK2/STAT5 signalling cascade, we then inhibited JAK2 activity using a new JAK2 inhibitor, TG101209. AHI-1 overexpression led to a reduction in the cellular response to the inhibitor while suppression of AHI-1 caused an increase in sensitivity in viability, apoptosis, and colony forming cell assays. Finally, a combination of IM and TG101209 was examined in the same K562 cells lines. Results from suggest that using a combination treatment approach was more effective at inhibiting cellular viability and colony formation than either treatment alone. These findings together suggest that AHI-1 may play an important role in mediating cellular resistance to IM and TG101209 and activates several BCR-ABL signalling pathways, and that it may be a vital target in eradicating the malignant leukemic cells arising in CML.

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2010-05-19

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/24851

Medical Genetics

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/