Targeting TKI-Insensitive CML Stem/Progenitor Cells By Effective Inhibition of a Novel PP2A-AHI-1-BCR-ABL-JAK2 Complex

• Published in: Blood 2014-12, Vol.124 (21), p.899-899
• Main Authors: Lai, Damian, Liu, Xiaohu, Chen, Min, Rothe, Katharina, Hu, Kaiji, Dunn, Sandra, Jiang, Xiaoyan
• Format: Article
• Language: English
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood.V124.21.899.899

Imatinib Mesylate (IM) and other ABL tyrosine kinase inhibitors (TKIs) have had a major impact on treatment of early phase CML patients. However, TKI monotherapies are not curative and initial and acquired resistance remain challenges. We demonstrated that CML stem cells are less responsive to TKIs and are a critical target population for TKI resistance. To prevent the development of resistant subclones, improved treatment approaches that target other elements active in CML stem cells are needed. One candidate is Abelson helper integration site-1 (AHI-1), an oncogene we identified that is upregulated in CML stem cells and interacts with multiple kinases, including BCR-ABL and JAK2. These complexes initiate BCR-ABL-transforming activity and mediate TKI response/resistance of CML stem/progenitor cells. Loss of these interactions significantly increases IM-sensitivity of CML stem/progenitor cells. These findings indicate that AHI-1 is a new therapeutic target in CML stem cells, but there are no specific small molecule inhibitors available that target AHI-1. By screening the Prestwick Chemical Library, we have recently identified a specific growth inhibitory compound that potentially targets AHI-1: Cantharidin (CAN), an inhibitor of protein phosphatase 2A (PP2A). CAN inhibited the growth of AHI-1-transduced cells by about 30% compared to control cells, but this effect was significantly enhanced to 93% with the addition of IM. As well, AHI-1-suppressed cells were more sensitive to CAN treatment, suggesting specific targeting of AHI-1 by a PP2A inhibitor. PP2A is a family of serine/threonine phosphatases that regulate numerous cell signaling cascades involved in proliferation and cell cycle control of cancer cells. It has been reported that PP2A activity can be upregulated or downregulated in cancer cells and can play either positive or negative roles in signaling pathways, suggesting that activation/suppression of PP2A activity and its specific pathways is differentially regulated in cancer cells. It has also been reported that PP2A activity is downregulated in CML cells, particularly in blast crisis CML, due to overexpression of SET, and that the use of a PP2A activator inhibits the growth of CML cells. Interestingly, we have now demonstrated that combination treatment with IM and CAN significantly prevents growth and induces apoptosis in CML K562 and IM-resistant K562 cells compared to single treatments (2-3 fold, p