Please use this identifier to cite or link to this item:
https://hdl.handle.net/2440/103601
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Type: | Journal article |
Title: | Combined targeting of JAK2 and Bcl-2/Bcl-xL to cure mutant JAK2-driven malignancies and overcome acquired resistance to JAK2 inhibitors |
Author: | Waibel, M. Solomon, V. Knight, D. Ralli, R. Kim, S. Banks, K. Vidacs, E. Virely, C. Sia, K. Bracken, L. Collins-Underwood, R. Drenberg, C. Ramsey, L. Meyer, S. Takiguchi, M. Dickins, R. Levine, R. Ghysdael, J. Dawson, M. Lock, R. et al. |
Citation: | Cell Reports, 2013; 5(4):1047-1059 |
Publisher: | Cell Press |
Issue Date: | 2013 |
ISSN: | 2211-1247 2211-1247 |
Statement of Responsibility: | 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 |
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. |
Keywords: | Cell Line, Tumor Animals Mice, Inbred C57BL Mice, Inbred NOD Humans Mice Mice, SCID Sulfonamides Biphenyl Compounds Nitrophenols Piperazines Pyrazoles Pyrimidines Membrane Proteins Proto-Oncogene Proteins Transplantation, Heterologous Gene Expression Profiling Neoplasm Transplantation Signal Transduction Apoptosis Cell Survival Drug Resistance, Neoplasm Apoptosis Regulatory Proteins bcl-X Protein Janus Kinase 2 Precursor T-Cell Lymphoblastic Leukemia-Lymphoma Bcl-2-Like Protein 11 |
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. |
DOI: | 10.1016/j.celrep.2013.10.038 |
Grant ID: | NHMRC |
Published version: | http://dx.doi.org/10.1016/j.celrep.2013.10.038 |
Appears in Collections: | Aurora harvest 3 Medicine publications |
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File | Description | Size | Format | |
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hdl_103601.pdf | Published version | 2.62 MB | Adobe PDF | View/Open |
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