Research Papers:

Hsp90 inhibition increases SOCS3 transcript and regulates migration and cell death in chronic lymphocytic leukemia

Timothy L. Chen _, Nikhil Gupta, Amy Lehman, Amy S. Ruppert, Lianbo Yu, Christopher C. Oakes, Rainer Claus, Christoph Plass, Kami J. Maddocks, Leslie Andritsos, Jeffery A. Jones, David M. Lucas, Amy J. Johnson, John C. Byrd and Erin Hertlein

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Oncotarget. 2016; 7:28684-28696. https://doi.org/10.18632/oncotarget.8760

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Timothy L. Chen1, Nikhil Gupta1, Amy Lehman2, Amy S. Ruppert1, Lianbo Yu2, Christopher C. Oakes1, Rainer Claus3,4, Christoph Plass4, Kami J. Maddocks1, Leslie Andritsos1, Jeffery A. Jones1, David M. Lucas1, Amy J. Johnson1, John C. Byrd1,5, Erin Hertlein1

1Department of Internal Medicine, Division of Hematology, Comprehensive Cancer Center at The Ohio State University, Columbus, Ohio, USA

2Center for Biostatistics, The Ohio State University, Columbus, Ohio, USA

3Department of Hematology, Oncology and Stem Cell Transplantation, University Medical Center Freiburg, Freiburg, Germany

4Division of Epigenomics and Cancer Risk Factors, German Cancer Research Center, Heidelberg, Germany

5Division of Medicinal Chemistry & Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, Ohio, USA

Correspondence to:

Erin Hertlein, email: [email protected]

Keywords: SOCS3, Hsp90, chronic lymphocytic leukemia

Received: September 22, 2015     Accepted: March 17, 2016     Published: April 16, 2016


Epigenetic or transcriptional silencing of important tumor suppressors has been described to contribute to cell survival and tumorigenesis in chronic lymphocytic leukemia (CLL). Using gene expression microarray analysis, we found that thousands of genes are repressed more than 2-fold in CLL compared to normal B cells; however therapeutic approaches to reverse this have been limited in CLL. Following treatment with the Hsp90 inhibitor 17-DMAG, a significant number of these repressed genes were significantly re-expressed. One of the genes significantly repressed in CLL and up-regulated by 17-DMAG was suppressor of cytokine signaling 3, (SOCS3). SOCS3 has been shown to be silenced in solid tumors as well as myeloid leukemia; however little is known about the regulation in CLL. We found that 17-DMAG induces expression of SOCS3 by via the activation of p38 signaling, and subsequently inhibits AKT and STAT3 phosphorylation resulting in downstream effects on cell migration and survival. We therefore suggest that SOCS3 is an important signaling protein in CLL, and Hsp90 inhibitors represent a novel approach to target transcriptional repression in B cell lymphoproliferative disorders which exhibit a substantial degree of gene repression.

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