title: Mechanisms and clinical significance of BIM phosphorylation in chronic lymphocytic leukemia.
abstract: B-cell receptor and microenvironment-derived signals promote accumulation of chronic lymphocytic leukemia (CLL) cells through increased proliferation and/or decreased apoptosis. In this study, we investigated the regulation of BIM, a proapoptotic BCL2-related protein, which is tightly regulated by phosphorylation. Surface IgM stimulation increased phosphorylation of 2 BIM isoforms, BIM(EL) and BIM(L), in a subset of CLL samples. In contrast, in normal B cells, anti-IgM triggered selective phosphorylation of BIM(EL) only. In CLL, anti-IgM-induced BIM phosphorylation correlated with unmutated IGHV gene status and with progressive disease. Strikingly, it was also associated with progressive disease within the mutated IGHV gene subset. BIM phosphorylation was dependent on MEK1/2 kinase activity, and we identified BIM(EL) serine 69, previously linked to pro-survival responses, as the major site of phosphorylation in CLL and in Ramos cells. BIM(EL)/BIM(L) phosphorylation was associated with release of the pro-survival protein MCL1. Coculture of CLL cells with HK cells, a model of the CLL microenvironment, promoted CLL cell survival and was associated with MEK1/2 activation and BIM(EL) phosphorylation. Hence, BIM phosphorylation appears to play a key role in apoptosis regulation in CLL cells, potentially coordinating antigen and microenvironment-derived survival signals. Antigen-mediated effects on BIM may be an important determinant of clinical behavior.
authors.affiliation: Cancer Research UK Centre, Cancer Sciences Unit, University of Southampton Faculty of Medicine, Southampton General Hospital, Southampton, United Kingdom.
authors.forename: Alex
authors.initials: A
authors.lastname: Paterson
authors.forename: C Ian
authors.initials: CI
authors.lastname: Mockridge
authors.forename: Jemimah E
authors.initials: JE
authors.lastname: Adams
authors.forename: Sergey
authors.initials: S
authors.lastname: Krysov
authors.forename: Kathleen N
authors.initials: KN
authors.lastname: Potter
authors.forename: Andrew S
authors.initials: AS
authors.lastname: Duncombe
authors.forename: Simon J
authors.initials: SJ
authors.lastname: Cook
authors.forename: Freda K
authors.initials: FK
authors.lastname: Stevenson
authors.forename: Graham
authors.initials: G
authors.lastname: Packham
mesh_terms: D000888:Antibodies, Anti-Idiotypic / Q000494:pharmacology; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D000072224:Bcl-2-Like Protein 11; D014408:Biomarkers, Tumor / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000175:diagnosis* / Q000378:metabolism*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D050505:Mutant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011379:Prognosis; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D059748:Proteolysis / Q000187:drug effects; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology
chemical_list: D000888:Antibodies, Anti-Idiotypic; D051017:Apoptosis Regulatory Proteins; C000606775:BCL2L11 protein, human; D000072224:Bcl-2-Like Protein 11; D014408:Biomarkers, Tumor; D008565:Membrane Proteins; D050505:Mutant Proteins; D020033:Protein Isoforms; D011518:Proto-Oncogene Proteins; C044203:anti-IgM; D048049:Extracellular Signal-Regulated MAP Kinases