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Mechanisms and clinical significance of BIM phosphorylation in chronic lymphocytic leukemia

Mechanisms and clinical significance of BIM phosphorylation in chronic lymphocytic leukemia
Mechanisms and clinical significance of BIM phosphorylation in chronic lymphocytic leukemia
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.

0006-4971
1726-1736
Paterson, Alex
0a9ef773-a7e7-4584-9c3c-db15754c3bd6
Mockridge, C.I.
327aef17-4837-4f2a-a93b-3d17cd1a7f9f
Adams, Jemimah E.
3a43c890-29ff-4cd5-bc38-ed6f05ed16f8
Krysov, Sergey
3a78eac1-af40-4b37-8576-3462947649be
Potter, Kathleen N.
86a99047-494b-405b-a3f7-650c1dcd5838
Dunscombe, Melanie S.
761f5609-1b0d-407f-b37e-0c64ef0fa54e
Cook, SJ
cc2a9c09-fe63-46f8-957a-4ef842f2d806
Stevenson, Freda K.
ba803747-c0ac-409f-a9c2-b61fde009f8c
Packham, Graham
fdabe56f-2c58-469c-aadf-38878f233394
Paterson, Alex
0a9ef773-a7e7-4584-9c3c-db15754c3bd6
Mockridge, C.I.
327aef17-4837-4f2a-a93b-3d17cd1a7f9f
Adams, Jemimah E.
3a43c890-29ff-4cd5-bc38-ed6f05ed16f8
Krysov, Sergey
3a78eac1-af40-4b37-8576-3462947649be
Potter, Kathleen N.
86a99047-494b-405b-a3f7-650c1dcd5838
Dunscombe, Melanie S.
761f5609-1b0d-407f-b37e-0c64ef0fa54e
Cook, SJ
cc2a9c09-fe63-46f8-957a-4ef842f2d806
Stevenson, Freda K.
ba803747-c0ac-409f-a9c2-b61fde009f8c
Packham, Graham
fdabe56f-2c58-469c-aadf-38878f233394

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), 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.

Full text not available from this repository.

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: https://eprints.soton.ac.uk/id/eprint/339296
ISSN: 0006-4971
PURE UUID: e35cf993-c738-4f4a-8f67-88eae036075f
ORCID for Freda K. Stevenson: ORCID iD orcid.org/0000-0002-0933-5021
ORCID for Graham Packham: ORCID iD orcid.org/0000-0002-9232-5691

Catalogue record

Date deposited: 28 May 2012 13:57
Last modified: 31 Jan 2019 01:37

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