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

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• 作者：Linfeng Chen¹ ; Stefano Monti³ ; ⁷ ; Przemyslaw Juszczynski¹ ; ⁸ ; Jing Ouyang¹ ; Bjoern Chapuy¹ ; Donna Neuberg² ; John G. Doench³ ; Agata M. Bogusz⁴ ; ⁹ ; Thomas M. Habermann⁵ ; Ahmet Dogan⁶ ; Thomas E. Witzig⁵ ; Jeffery L. Kutok⁴ ; ¹⁰ ; Scott J. Rodig⁴ ; Todd Golub³ ; Margaret A. Shipp¹ ; ^{margaret_shipp@dfci.harvard.edu}
• 刊名：Cancer Cell
• 出版年：2013
• 出版时间：10 June, 2013
• 年：2013
• 卷：23
• 期：6
• 页码：826-838
• 全文大小：3096 K

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Summary

B cell receptor (BCR) signaling pathway components represent promising treatment targets in diffuse large B?cell lymphoma (DLBCL) and additional B cell tumors. BCR signaling activates spleen tyrosine kinase (SYK) and downstream pathways including PI3K/AKT and NF-¦ÊB. 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-¦ÊB activity including selective repression of the pro-apoptotic HRK protein in NF-¦ÊB-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-¦ÊB. In addition, SYK amplification and PTEN deletion are identified as selective genetic alterations in primary ¡°BCR¡±-type DLBCLs.