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 B cell 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.
authors.affiliation: Department of Medical Oncology, Dana Farber Cancer Institute, Boston, MA 02215, USA.
authors.forename: Linfeng
authors.initials: L
authors.lastname: Chen
authors.forename: Stefano
authors.initials: S
authors.lastname: Monti
authors.forename: Przemyslaw
authors.initials: P
authors.lastname: Juszczynski
authors.forename: Jing
authors.initials: J
authors.lastname: Ouyang
authors.forename: Bjoern
authors.initials: B
authors.lastname: Chapuy
authors.forename: Donna
authors.initials: D
authors.lastname: Neuberg
authors.forename: John G
authors.initials: JG
authors.lastname: Doench
authors.forename: Agata M
authors.initials: AM
authors.lastname: Bogusz
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Habermann
authors.forename: Ahmet
authors.initials: A
authors.lastname: Dogan
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Witzig
authors.forename: Jeffery L
authors.initials: JL
authors.lastname: Kutok
authors.forename: Scott J
authors.initials: SJ
authors.lastname: Rodig
authors.forename: Todd
authors.initials: T
authors.lastname: Golub
authors.forename: Margaret A
authors.initials: MA
authors.lastname: Shipp
mesh_terms: D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002784:Cholesterol / Q000096:biosynthesis; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000378:metabolism / Q000502:physiology; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors*; D016403:Lymphoma, Large B-Cell, Diffuse / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051562:Proto-Oncogene Proteins c-bcr / Q000378:metabolism*; D015398:Signal Transduction; D000072377:Syk Kinase
chemical_list: D051017:Apoptosis Regulatory Proteins; C085126:FOXO1 protein, human; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C484586:HRK protein, human; D047908:Intracellular Signaling Peptides and Proteins; D016328:NF-kappa B; D002784:Cholesterol; D058539:Phosphatidylinositol 3-Kinase; D011505:Protein-Tyrosine Kinases; C000606896:SYK protein, human; D000072377:Syk Kinase; C496613:BCR protein, human; D051057:Proto-Oncogene Proteins c-akt; D051562:Proto-Oncogene Proteins c-bcr