PP2A-activating drugs selectively eradicate TKI-resistant chronic myeloid leukemic stem cells
| Autor: | Jacek Bielawski, Adrienne M. Dorrance, William Blum, Jason G. Harb, Rebecca B. Klisovic, Alistair Reid, Paolo Neviani, Stefano Volinia, Dragana Milojkovic, Carolyn Paisie, Mark Wunderlich, Ramasamy Santhanam, Denis-Claude Roy, Steffen Koschmieder, James C. Mulloy, Sahar A. Saddoughi, Ching-Shih Chen, Tessa L. Holyoake, Anna M. Eiring, Yihui Ma, Peter Hokland, Joshua J. Oaks, Jorge E. Cortes, Carlo M. Croce, Claudia S. Huettner, Steven M. Devine, Christopher J. Walker, Janelle A. Solt, Jane F. Apperley, Michael A. Caligiuri, Guido Marcucci, Hsiaoyin C. Mao, Justin Ellis, Ralph B. Arlinghaus, John M. Goldman, Bin Zhang, Ramiro Garzon, Ravi Bhatia, Chaode Sun, Gregory Ferenchak, Besim Ogretmen, Robert Bittman, Danilo Perrotti, John C. Byrd, Philippa C. May |
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| Rok vydání: | 2013 |
| Předmět: |
Disease reservoir
Myeloid Fusion Proteins bcr-abl Drug Resistance Apoptosis Mice Sphingosine hemic and lymphatic diseases Protein Phosphatase 2 Wnt Signaling Pathway beta Catenin Leukemia Myeloid leukemia General Medicine drug therapy medicine.anatomical_structure Neoplastic Stem Cells Stem cell Animals Antineoplastic Agents pharmacology Apoptosis Cell Proliferation drug effects Drug Resistance Neoplasm Enzyme Activators pharmacology Fusion Proteins drug effects/enzymology Humans Janus Kinase 2 metabolism K562 Cells Leukemia Myelogenous BCR-ABL Positive drug therapy Mice Neoplastic Stem Cells drug effects/enzymology Propylene Glycols pharmacology Protein Phosphatase 2 metabolism Sphingosine Tyrosine kinase Research Article Cell Survival Enzyme Activators Mice Transgenic Antineoplastic Agents Biology drug effects/enzymology NO Leukemia Myelogenous Chronic BCR-ABL Positive medicine Animals Humans Kinase activity Progenitor cell Protein Kinase Inhibitors Cell Proliferation Fingolimod Hydrochloride Fusion Proteins Janus Kinase 2 Hematopoietic Stem Cells medicine.disease Xenograft Model Antitumor Assays Drug Resistance Neoplasm Propylene Glycols drug effects Immunology Neoplasm pharmacology K562 Cells metabolism |
| Zdroj: | 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-S, Bittman, R, Hokland, P, Roy, D-C, Milojkovic, D, Apperley, J, Goldman, J M, Reid, A, Mulloy, J C, Bhatia, R, Marcucci, G & Perrotti, D 2013, ' PP2A-activating drugs selectively eradicate TKI-resistant chronic myeloid leukemic stem cells ', Journal of Clinical Investigation, vol. 123, no. 10, pp. 4144-57 . https://doi.org/10.1172/JCI68951 |
| ISSN: | 0021-9738 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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