PP2A-activating drugs selectively eradicate TKI-resistant chronic myeloid leukemic stem cells

Neviani, P. et al. (2013) PP2A-activating drugs selectively eradicate TKI-resistant chronic myeloid leukemic stem cells. Journal of Clinical Investigation, 123(10), pp. 4144-4157. (doi: 10.1172/JCI68951)

Abstract

The success of tyrosine kinase inhibitors (TKIs) in treating chronic myeloid leukemia (CML) depends on the requirement for BCR-ABL1 kinase activity in CML progenitors. However, CML quiescent HSCs are TKI resistant and represent a BCR-ABL1 kinase–independent disease reservoir. Here we have shown that persistence of leukemic HSCs in BM requires inhibition of the tumor suppressor protein phosphatase 2A (PP2A) and expression — but not activity — of the BCR-ABL1 oncogene. Examination of HSCs from CML patients and healthy individuals revealed that PP2A activity was suppressed in CML compared with normal HSCs. TKI-resistant CML quiescent HSCs showed increased levels of BCR-ABL1, but very low kinase activity. BCR-ABL1 expression, but not kinase function, was required for recruitment of JAK2, activation of a JAK2/β-catenin survival/self-renewal pathway, and inhibition of PP2A. PP2A-activating drugs (PADs) markedly reduced survival and self-renewal of CML quiescent HSCs, but not normal quiescent HSCs, through BCR-ABL1 kinase–independent and PP2A-mediated inhibition of JAK2 and β-catenin. This led to suppression of human leukemic, but not normal, HSC/progenitor survival in BM xenografts and interference with long-term maintenance of BCR-ABL1–positive HSCs in serial transplantation assays. Targeting the JAK2/PP2A/β-catenin network in quiescent HSCs with PADs (e.g., FTY720) has the potential to treat TKI-refractory CML and relieve lifelong patient dependence on TKIs.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Holyoake, Professor Tessa
• Authors: Neviani, P., Harb, J.G., Oaks, J.J., Santhanam, R., Walker, C.J., Ellis, J.J., Ferenchak, G., Dorrance, A.M., Paisie, C.A., Eiring, A.M., Ma, Y., Mao, H.C., Zhang, B., Wunderlich, M., May, P.C., Sun, C., Saddoughi, S.A., Bielawski, J., Blum, W., Klisovic, R.B., Solt, J.A., Byrd, J.C., Volinia, S., Cortes, J., Huettner, C.S., Koschmieder, S., Holyoake, T.L., Devine, S., Caligiuri, M.A., Croce, C.M., Garzon, R., Ogretmen, B., Arlinghaus, R.B., Chen, C., Bittman, R., Hokland, P., Roy, D., Milojkovic, D., Apperley, J., Goldman, J.M., Reid, A., Mulloy, J.C., Bhatia, R., Marcucci, G., and Perrotti, D.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Journal Name: Journal of Clinical Investigation
• Publisher: Americal Society for Clinical Investigation
• ISSN: 0021-9738
• ISSN (Online): 1558-8238