SYK Inhibition Modulates Distinct PI3K/AKT- Dependent Survival Pathways and Cholesterol Biosynthesis in Diffuse Large B Cell Lymphomas

Linfeng Chen, Stefano Monti, Przemyslaw Juszczynski, Jing Ouyang, Bjoern Chapuy, Donna Neuberg, John G. Doench, Agata M. Bogusz, Thomas M. Habermann, Ahmet Dogan, Thomas E. Witzig, Jeffery L. Kutok, Scott J. Rodig, Todd Golub, Margaret A. Shipp

Research output: Contribution to journalArticle

99 Scopus citations

Abstract

B cell receptor (BCR) signaling pathway components represent promising treatment targets in diffuse large Bcell lymphoma (DLBCL) and additional B cell tumors. BCR signaling activates spleen tyrosine kinase (SYK) and downstream pathways including PI3K/AKT and NF-κB. In previous studies, chemical SYK blockade selectively decreased BCR signaling and induced apoptosis of BCR-dependent DLBCLs. Herein, we characterize distinct SYK/PI3K-dependent survival pathways in DLBCLs with high or low baseline NF-κB activity including selective repression of the pro-apoptotic HRK protein in NF-κB-low tumors. We also define SYK/PI3K-dependent cholesterol biosynthesis as a feed-forward mechanism of maintaining the integrity of BCRs in lipid rafts in DLBCLs with low or high NF-κB. In addition, SYK amplification and PTEN deletion are identified as selective genetic alterations in primary "BCR"-type DLBCLs.

Original languageEnglish (US)
Pages (from-to)826-838
Number of pages13
JournalCancer cell
Volume23
Issue number6
DOIs
StatePublished - Jun 10 2013

ASJC Scopus subject areas

  • Oncology
  • Cell Biology
  • Cancer Research

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    Chen, L., Monti, S., Juszczynski, P., Ouyang, J., Chapuy, B., Neuberg, D., Doench, J. G., Bogusz, A. M., Habermann, T. M., Dogan, A., Witzig, T. E., Kutok, J. L., Rodig, S. J., Golub, T., & Shipp, M. A. (2013). SYK Inhibition Modulates Distinct PI3K/AKT- Dependent Survival Pathways and Cholesterol Biosynthesis in Diffuse Large B Cell Lymphomas. Cancer cell, 23(6), 826-838. https://doi.org/10.1016/j.ccr.2013.05.002