Journal Article

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

Sun, Chaode, Santhanam, Ramasamy, Bhatia, Ravi, Dorrance, Adrienne M., Ma, Yihui, Oaks, Joshua J., Walker, Christopher J., Solt, Janelle A., May, Philippa C., Reid, Alistair, Wunderlich, Mark, Garzon, Ramiro, Mulloy, James C., Bielawski, Jacek, Klisovic, Rebecca B., Cortes, Jorge, Koschmieder, Steffen, Blum, William, Saddoughi, Sahar A., Devine, Steven, Harb, Jason G., Croce, Carlo M., Paisie, Carolyn A., Eiring, Anna M., Caligiuri, Michael A., Holyoake, Tessa L., Ferenchak, Gregory, Bittman, Robert, Roy, Denis-Claude, Marcucci, Guido, Hokland, Peter, Mao, Hsiaoyin C., Chen, Ching-Shih, Perrotti, Danilo, Huettner, Claudia S., Byrd, John C., Ogretmen, Besim, Goldman, John M., Ellis, Justin J., Neviani, Paolo, Arlinghaus, Ralph B., Apperley, Jane, Zhang, Bin, Milojkovic, Dragana, Volinia, Stefano

2013

Overview

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.

• Publisher: American Society for Clinical Investigation
• Subject: Animals / Antineoplastic Agents - pharmacology / Apoptosis / BCR-ABL tyrosine kinase inhibitors / beta Catenin - metabolism / Biomedical research / Cancer / Cancer therapies / Cell Proliferation - drug effects / Cell Survival - drug effects / Chronic myeloid leukemia / Dosage and administration / Drug resistance / Drug Resistance, Neoplasm / Drug therapy / Enzyme Activators - pharmacology / Fingolimod Hydrochloride / Fusion Proteins, bcr-abl - metabolism / Grants / Hematopoietic Stem Cells - drug effects / Hematopoietic Stem Cells - enzymology / Humans / Janus Kinase 2 - metabolism / K562 Cells / Kinases / Leukemia / Leukemia, Myelogenous, Chronic, BCR-ABL Positive - drug therapy / Lymphoma / Medical research / Mice / Mice, Transgenic / Neoplastic Stem Cells - drug effects / Neoplastic Stem Cells - enzymology / Propylene Glycols - pharmacology / Protein Kinase Inhibitors - pharmacology / Protein Phosphatase 2 - metabolism / Sphingosine - analogs & derivatives / Sphingosine - pharmacology / Stem cells / Wnt Signaling Pathway / Xenograft Model Antitumor Assays