Journal
CELL REPORTS
Volume 5, Issue 4, Pages 1047-1059Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2013.10.038
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Funding
- NHMRC
- Susan G. Komen Breast Cancer Foundation
- Prostate Cancer Foundation of Australia
- Cancer Council Victoria
- Leukemia Foundation of Australia
- Victorian Breast Cancer Research Consortium
- Victorian Cancer Agency
- Australian Rotary Health Foundation
- Deutsche Forschungsgemeinschaft
- Peter MacCallum Cancer Foundation
- Bioplatforms Australia
- Swiss National Science Foundation
- Huggenberger-Bischoff Foundation for Cancer Research
- ALSAC of St. Jude Children's Research Hospital
- Pew Charitable Trusts
- Institute Curie
- CNRS
- INSERM
- INCA
- Ligue Contre le Cancer (Equipe labellisee Ligue)
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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.
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