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

doi:10.1016/j.ccr.2013.05.002

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

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111 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 language	English (US)
Pages (from-to)	826-838
Number of pages	13
Journal	Cancer cell
Volume	23
Issue number	6
DOIs	https://doi.org/10.1016/j.ccr.2013.05.002
State	Published - Jun 10 2013

ASJC Scopus subject areas

Oncology
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

Chen, L, Monti, S, Juszczynski, P, Ouyang, J, Chapuy, B, Neuberg, D, Doench, JG, Bogusz, AM, Habermann, TM, Dogan, A, Witzig, TE, Kutok, JL, Rodig, SJ, Golub, T & Shipp, MA 2013, 'SYK Inhibition Modulates Distinct PI3K/AKT- Dependent Survival Pathways and Cholesterol Biosynthesis in Diffuse Large B Cell Lymphomas', Cancer cell, vol. 23, no. 6, pp. 826-838. https://doi.org/10.1016/j.ccr.2013.05.002

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

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.",

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

note = "Funding Information: This work was supported by NIH grants P01CA092625, LLS SCOR 7391, and LLS SCOR 7009. ",

year = "2013",

month = jun,

day = "10",

doi = "10.1016/j.ccr.2013.05.002",

language = "English (US)",

volume = "23",

pages = "826--838",

journal = "Cancer cell",

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T1 - SYK Inhibition Modulates Distinct PI3K/AKT- Dependent Survival Pathways and Cholesterol Biosynthesis in Diffuse Large B Cell Lymphomas

AU - Chen, Linfeng

AU - Monti, Stefano

AU - Juszczynski, Przemyslaw

AU - Ouyang, Jing

AU - Chapuy, Bjoern

AU - Neuberg, Donna

AU - Doench, John G.

AU - Bogusz, Agata M.

AU - Habermann, Thomas M.

AU - Dogan, Ahmet

AU - Witzig, Thomas E.

AU - Kutok, Jeffery L.

AU - Rodig, Scott J.

AU - Golub, Todd

AU - Shipp, Margaret A.

N1 - Funding Information: This work was supported by NIH grants P01CA092625, LLS SCOR 7391, and LLS SCOR 7009.

PY - 2013/6/10

Y1 - 2013/6/10

N2 - 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.

AB - 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.

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JF - Cancer cell

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

Abstract

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