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Yuzugullu H, Von T, Thorpe LM, et al. NTRK2 activation cooperates with PTEN deficiency in T-ALL through activation of both the PI3K-AKT and JAK-STAT3 pathways. Cell Discov. 2016;2:16030doi: 10.1038/celldisc.2016.30.
Yuzugullu, H., Von, T., Thorpe, L. M., Walker, S. R., Roberts, T. M., Frank, D. A., & Zhao, J. J. (2016). NTRK2 activation cooperates with PTEN deficiency in T-ALL through activation of both the PI3K-AKT and JAK-STAT3 pathways. Cell discovery, 216030. https://doi.org/10.1038/celldisc.2016.30
Yuzugullu, Haluk, et al. "NTRK2 activation cooperates with PTEN deficiency in T-ALL through activation of both the PI3K-AKT and JAK-STAT3 pathways." Cell discovery vol. 2 (2016): 16030. doi: https://doi.org/10.1038/celldisc.2016.30
Yuzugullu H, Von T, Thorpe LM, Walker SR, Roberts TM, Frank DA, Zhao JJ. NTRK2 activation cooperates with PTEN deficiency in T-ALL through activation of both the PI3K-AKT and JAK-STAT3 pathways. Cell Discov. 2016 Sep 20;2:16030. doi: 10.1038/celldisc.2016.30. eCollection 2016. PMID: 27672444; PMCID: PMC5029543.
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Cell Discov. 2016 Sep 20;2:16030. doi: 10.1038/celldisc.2016.30. eCollection 2016.

NTRK2 activation cooperates with PTEN deficiency in T-ALL through activation of both the PI3K-AKT and JAK-STAT3 pathways.

Cell discovery

Haluk Yuzugullu, Thanh Von, Lauren M Thorpe, Sarah R Walker, Thomas M Roberts, David A Frank, Jean J Zhao

Affiliations

  1. Department of Cancer Biology, Dana Farber Cancer Institute, Boston, MA, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA.
  2. Department of Medical Oncology, Dana Farber Cancer Institute, Boston, MA, USA; Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.

PMID: 27672444 PMCID: PMC5029543 DOI: 10.1038/celldisc.2016.30

Abstract

Loss of PTEN, a negative regulator of the phosphoinositide 3-kinase signaling pathway, is a frequent event in T-cell acute lymphoblastic leukemia, suggesting the importance of phosphoinositide 3-kinase activity in this disease. Indeed, hyperactivation of the phosphoinositide 3-kinase pathway is associated with the disease aggressiveness, poor prognosis and resistance to current therapies. To identify a molecular pathway capable of cooperating with PTEN deficiency to drive oncogenic transformation of leukocytes, we performed an unbiased transformation screen with a library of tyrosine kinases. We found that activation of NTRK2 is able to confer a full growth phenotype of Ba/F3 cells in an IL3-independent manner in the PTEN-null setting. NTRK2 activation cooperates with PTEN deficiency through engaging both phosphoinositide3-kinase/AKT and JAK/STAT3 pathway activation in leukocytes. Notably, pharmacological inhibition demonstrated that p110α and p110δ are the major isoforms mediating the phosphoinositide 3-kinase/AKT signaling driven by NTRK2 activation in PTEN-deficient leukemia cells. Furthermore, combined inhibition of phosphoinositide 3-kinase and STAT3 significantly suppressed proliferation of PTEN-mutant T-cell acute lymphoblastic leukemia both in culture and in mouse xenografts. Together, our data suggest that a unique conjunction of PTEN deficiency and NTRK2 activation in T-cell acute lymphoblastic leukemia, and combined pharmacologic inhibition of phosphoinositide 3-kinase and STAT3 signaling may serve as an effective and durable therapeutic strategy for T-cell acute lymphoblastic leukemia.

Keywords: NTRK2; PI3K; PTEN; STAT-3; T-ALL; targeted therapy

Conflict of interest statement

TMR is a consultant of Novartis and has received a research grant from Novartis. The remaining authors declare no competing financial interests.

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