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Mechanisms and clinical significance of BIM phosphorylation in chronic lymphocytic leukemia

Paterson, Alex, Mockridge, C.I., Adams, Jemimah E., Krysov, Sergey, Potter, Kathleen N., Dunscombe, Melanie S., Cook, SJ, Stevenson, Freda K. and Packham, Graham (2012) Mechanisms and clinical significance of BIM phosphorylation in chronic lymphocytic leukemia Blood, 119, (7), pp. 1726-1736. (doi:10.1182/blood-2011-07-367417). (PMID:22160382).

Record type: Article

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, BIMEL and BIML, in a subset of CLL samples. In contrast, in normal B cells, anti-IgM triggered selective phosphorylation of BIMEL 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 BIMEL serine 69, previously linked to pro-survival responses, as the major site of phosphorylation in CLL and in Ramos cells. BIMEL/BIML 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 BIMEL 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.

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More information

e-pub ahead of print date: 7 December 2011
Published date: 16 February 2012
Organisations: Cancer Sciences

Identifiers

Local EPrints ID: 339296
URI: http://eprints.soton.ac.uk/id/eprint/339296
ISSN: 0006-4971
PURE UUID: e35cf993-c738-4f4a-8f67-88eae036075f

Catalogue record

Date deposited: 28 May 2012 13:57
Last modified: 01 Sep 2017 16:32

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Contributors

Author: Alex Paterson
Author: C.I. Mockridge
Author: Jemimah E. Adams
Author: Sergey Krysov
Author: Melanie S. Dunscombe
Author: SJ Cook
Author: Graham Packham

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