title: Surface IgM stimulation induces MEK1/2-dependent MYC expression in chronic lymphocytic leukemia cells.
abstract: Although long considered as a disease of failed apoptosis, it is now clear that chronic lymphocytic leukemia (CLL) cells undergo extensive cell division in vivo, especially in progressive disease. Signaling via the B-cell receptor is thought to activate proliferation and survival pathways in CLL cells and also has been linked to poor outcome. Here, we have analyzed the expression of the proto-oncoprotein MYC, an essential positive regulator of the cell cycle, after stimulation of surface IgM (sIgM). MYC expression was rapidly increased after sIgM stimulation in a subset of CLL samples. The ability of sIgM stimulation to increase MYC expression was correlated with sIgM-induced intracellular calcium fluxes. MYC induction was partially dependent on the MEK/ERK signaling pathway, and MYC and phosphorylated ERK1/2 were both expressed within proliferation centers in vivo. Although stimulation of sIgD also resulted in ERK1/2 phosphorylation, responses were relatively short lived compared with sIgM and were associated with significantly reduced MYC induction, suggesting that the kinetics of ERK1/2 activation is a critical determinant of MYC induction. Our results suggest that ERK1/2-dependent induction of MYC is likely to play an important role in antigen-induced CLL cell proliferation.
authors.affiliation: Cancer Research UK Centre, Cancer Sciences Division, University of Southampton School of Medicine, Southampton General Hospital, Southampton, United Kingdom. s.krysov@soton.ac.uk
authors.forename: Sergey
authors.initials: S
authors.lastname: Krysov
authors.forename: Samantha
authors.initials: S
authors.lastname: Dias
authors.forename: Alex
authors.initials: A
authors.lastname: Paterson
authors.forename: C Ian
authors.initials: CI
authors.lastname: Mockridge
authors.forename: Kathleen N
authors.initials: KN
authors.lastname: Potter
authors.forename: Kelly-Ann
authors.initials: KA
authors.lastname: Smith
authors.forename: Margaret
authors.initials: M
authors.lastname: Ashton-Key
authors.forename: Freda K
authors.initials: FK
authors.lastname: Stevenson
authors.forename: Graham
authors.initials: G
authors.lastname: Packham
mesh_terms: D015153:Blotting, Western; D002453:Cell Cycle; D002462:Cell Membrane / Q000378:metabolism*; D049109:Cell Proliferation; D006801:Humans; D007124:Immunoenzyme Techniques; D007075:Immunoglobulin M / Q000378:metabolism*; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D048369:MAP Kinase Kinase 1 / Q000235:genetics / Q000378:metabolism*; D048370:MAP Kinase Kinase 2 / Q000235:genetics / Q000378:metabolism*; D019950:Mitogen-Activated Protein Kinase 1 / Q000235:genetics / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000235:genetics / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D014407:Tumor Cells, Cultured
chemical_list: D007075:Immunoglobulin M; C489427:MYC protein, human; D016271:Proto-Oncogene Proteins c-myc; D012333:RNA, Messenger; C482128:MAP2K2 protein, human; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2; C482125:MAP2K1 protein, human