Please use this identifier to cite or link to this item:
https://hdl.handle.net/2440/103601
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dc.contributor.author | Waibel, M. | - |
dc.contributor.author | Solomon, V. | - |
dc.contributor.author | Knight, D. | - |
dc.contributor.author | Ralli, R. | - |
dc.contributor.author | Kim, S. | - |
dc.contributor.author | Banks, K. | - |
dc.contributor.author | Vidacs, E. | - |
dc.contributor.author | Virely, C. | - |
dc.contributor.author | Sia, K. | - |
dc.contributor.author | Bracken, L. | - |
dc.contributor.author | Collins-Underwood, R. | - |
dc.contributor.author | Drenberg, C. | - |
dc.contributor.author | Ramsey, L. | - |
dc.contributor.author | Meyer, S. | - |
dc.contributor.author | Takiguchi, M. | - |
dc.contributor.author | Dickins, R. | - |
dc.contributor.author | Levine, R. | - |
dc.contributor.author | Ghysdael, J. | - |
dc.contributor.author | Dawson, M. | - |
dc.contributor.author | Lock, R. | - |
dc.contributor.author | et al. | - |
dc.date.issued | 2013 | - |
dc.identifier.citation | Cell Reports, 2013; 5(4):1047-1059 | - |
dc.identifier.issn | 2211-1247 | - |
dc.identifier.issn | 2211-1247 | - |
dc.identifier.uri | http://hdl.handle.net/2440/103601 | - |
dc.description.abstract | To design rational therapies for JAK2-driven hematological malignancies, we functionally dissected the key survival pathways downstream of hyperactive JAK2. In tumors driven by mutant JAK2, Stat1, Stat3, Stat5, and the Pi3k and Mek/Erk pathways were constitutively active, and gene expression profiling of TEL-JAK2 T-ALL cells revealed the upregulation of prosurvival Bcl-2 family genes. Combining the Bcl-2/Bcl-xL inhibitor ABT-737 with JAK2 inhibitors mediated prolonged disease regressions and cures in mice bearing primary human and mouse JAK2 mutant tumors. Moreover, combined targeting of JAK2 and Bcl-2/Bcl-xL was able to circumvent and overcome acquired resistance to single-agent JAK2 inhibitor treatment. Thus, inhibiting the oncogenic JAK2 signaling network at two nodal points, at the initiating stage (JAK2) and the effector stage (Bcl-2/Bcl-xL), is highly effective and provides a clearly superior therapeutic benefit than targeting just one node. Therefore, we have defined a potentially curative treatment for hematological malignancies expressing constitutively active JAK2. | - |
dc.description.statementofresponsibility | Michaela Waibel, Vanessa S. Solomon, Deborah A. Knight, Rachael A. Ralli, Sang-Kyu Kim, Kellie-Marie Banks, Eva Vidacs, Clemence Virely, Keith C.S. Sia, Lauryn S. Bracken, Racquel Collins-Underwood, Christina Drenberg, Laura B. Ramsey, Sara C. Meyer, Megumi Takiguchi, Ross A. Dickins, Ross Levine, Jacques Ghysdael, Mark A. Dawson, Richard B. Lock, Charles G. Mullighan and Ricky W. Johnstone | - |
dc.language.iso | en | - |
dc.publisher | Cell Press | - |
dc.rights | ©2013 The Authors, This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial-No Derivative Works License, which permits non-commercial use, distribution, and reproduction in any medium, provided the original author and source are credited. | - |
dc.source.uri | http://dx.doi.org/10.1016/j.celrep.2013.10.038 | - |
dc.subject | Cell Line, Tumor | - |
dc.subject | Animals | - |
dc.subject | Mice, Inbred C57BL | - |
dc.subject | Mice, Inbred NOD | - |
dc.subject | Humans | - |
dc.subject | Mice | - |
dc.subject | Mice, SCID | - |
dc.subject | Sulfonamides | - |
dc.subject | Biphenyl Compounds | - |
dc.subject | Nitrophenols | - |
dc.subject | Piperazines | - |
dc.subject | Pyrazoles | - |
dc.subject | Pyrimidines | - |
dc.subject | Membrane Proteins | - |
dc.subject | Proto-Oncogene Proteins | - |
dc.subject | Transplantation, Heterologous | - |
dc.subject | Gene Expression Profiling | - |
dc.subject | Neoplasm Transplantation | - |
dc.subject | Signal Transduction | - |
dc.subject | Apoptosis | - |
dc.subject | Cell Survival | - |
dc.subject | Drug Resistance, Neoplasm | - |
dc.subject | Apoptosis Regulatory Proteins | - |
dc.subject | bcl-X Protein | - |
dc.subject | Janus Kinase 2 | - |
dc.subject | Precursor T-Cell Lymphoblastic Leukemia-Lymphoma | - |
dc.subject | Bcl-2-Like Protein 11 | - |
dc.title | Combined targeting of JAK2 and Bcl-2/Bcl-xL to cure mutant JAK2-driven malignancies and overcome acquired resistance to JAK2 inhibitors | - |
dc.type | Journal article | - |
dc.identifier.doi | 10.1016/j.celrep.2013.10.038 | - |
dc.relation.grant | NHMRC | - |
pubs.publication-status | Published | - |
dc.identifier.orcid | Mullighan, C. [0000-0002-1871-1850] | - |
Appears in Collections: | Aurora harvest 3 Medicine publications |
Files in This Item:
File | Description | Size | Format | |
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hdl_103601.pdf | Published version | 2.62 MB | Adobe PDF | View/Open |
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