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Stimulation of surface IgM of chronic lymphocytic leukemia cells induces an unfolded protein response dependent on BTK and SYK

Stimulation of surface IgM of chronic lymphocytic leukemia cells induces an unfolded protein response dependent on BTK and SYK
Stimulation of surface IgM of chronic lymphocytic leukemia cells induces an unfolded protein response dependent on BTK and SYK
B-cell receptor (BCR) signaling plays a key role in the behavior of chronic lymphocytic leukemia (CLL). However, cellular consequences of signaling are incompletely defined. Here we explored possible links between BCR signaling and the unfolded protein response (UPR), a stress response pathway that can promote survival of normal and malignant cells. Compared with normal B cells, circulating CLL cells expressed increased, but variable, levels of UPR components. Higher expression of CHOP and XBP1 RNAs was associated with more aggressive disease. UPR activation appeared due to prior tissue-based antigenic stimulation because elevated expression of UPR components was detected within lymph node proliferation centers. Basal UPR activation also correlated closely with surface immunoglobulin M (sIgM) signaling capacity in vitro in both IGHV unmutated CLL and within mutated CLL. sIgM signaling increased UPR activation in vitro with responders showing increased expression of CHOP and XBP1 RNAs, and PERK and BIP proteins, but not XBP1 splicing. Inhibitors of BCR-associated kinases effectively prevented sIgM-induced UPR activation. Overall, this study demonstrates that sIgM signaling results in activation of some components the UPR in CLL cells. Modulation of the UPR may contribute to variable clinical behavior, and its inhibition may contribute to clinical responses to BCR-associated kinase inhibitors.
0006-4971
3101-3109
Krysov, Sergey
3a78eac1-af40-4b37-8576-3462947649be
Steele, Andrew J.
4349f6aa-2e3a-49a8-be73-7716056ae089
Coelho, Vania
f037a720-66df-49fd-880a-9015155f72c4
Linley, Adam
10879190-27e3-42a9-a28b-3f8d7724e439
Hidalgo, Marina Sanchez
31973e11-d5d4-4dca-b1e2-18f08780c7c4
Carter, Matthew
3baac102-d80c-42ba-ab4d-ad339a48169e
Potter, Kathleen N.
86a99047-494b-405b-a3f7-650c1dcd5838
Kennedy, Benjamin
8c3c561f-7a07-4b85-878d-b65150fbddac
Duncombe, Andrew S.
ce7cb7e9-5aec-4801-ab3c-18b4de474fef
Ashton-Key, Margaret
5111ac18-7d4f-4ef0-9c71-0a44c37aaed4
Forconi, Francesco
ce9ed873-58cf-4876-bf3a-9ba1d163edc8
Stevenson, Freda K.
ba803747-c0ac-409f-a9c2-b61fde009f8c
Packham, Graham
fdabe56f-2c58-469c-aadf-38878f233394
Krysov, Sergey
3a78eac1-af40-4b37-8576-3462947649be
Steele, Andrew J.
4349f6aa-2e3a-49a8-be73-7716056ae089
Coelho, Vania
f037a720-66df-49fd-880a-9015155f72c4
Linley, Adam
10879190-27e3-42a9-a28b-3f8d7724e439
Hidalgo, Marina Sanchez
31973e11-d5d4-4dca-b1e2-18f08780c7c4
Carter, Matthew
3baac102-d80c-42ba-ab4d-ad339a48169e
Potter, Kathleen N.
86a99047-494b-405b-a3f7-650c1dcd5838
Kennedy, Benjamin
8c3c561f-7a07-4b85-878d-b65150fbddac
Duncombe, Andrew S.
ce7cb7e9-5aec-4801-ab3c-18b4de474fef
Ashton-Key, Margaret
5111ac18-7d4f-4ef0-9c71-0a44c37aaed4
Forconi, Francesco
ce9ed873-58cf-4876-bf3a-9ba1d163edc8
Stevenson, Freda K.
ba803747-c0ac-409f-a9c2-b61fde009f8c
Packham, Graham
fdabe56f-2c58-469c-aadf-38878f233394

Krysov, Sergey, Steele, Andrew J., Coelho, Vania, Linley, Adam, Hidalgo, Marina Sanchez, Carter, Matthew, Potter, Kathleen N., Kennedy, Benjamin, Duncombe, Andrew S., Ashton-Key, Margaret, Forconi, Francesco, Stevenson, Freda K. and Packham, Graham (2014) Stimulation of surface IgM of chronic lymphocytic leukemia cells induces an unfolded protein response dependent on BTK and SYK. Blood, 124 (20), 3101-3109. (doi:10.1182/blood-2014-04-567198). (PMID:25170122)

Record type: Article

Abstract

B-cell receptor (BCR) signaling plays a key role in the behavior of chronic lymphocytic leukemia (CLL). However, cellular consequences of signaling are incompletely defined. Here we explored possible links between BCR signaling and the unfolded protein response (UPR), a stress response pathway that can promote survival of normal and malignant cells. Compared with normal B cells, circulating CLL cells expressed increased, but variable, levels of UPR components. Higher expression of CHOP and XBP1 RNAs was associated with more aggressive disease. UPR activation appeared due to prior tissue-based antigenic stimulation because elevated expression of UPR components was detected within lymph node proliferation centers. Basal UPR activation also correlated closely with surface immunoglobulin M (sIgM) signaling capacity in vitro in both IGHV unmutated CLL and within mutated CLL. sIgM signaling increased UPR activation in vitro with responders showing increased expression of CHOP and XBP1 RNAs, and PERK and BIP proteins, but not XBP1 splicing. Inhibitors of BCR-associated kinases effectively prevented sIgM-induced UPR activation. Overall, this study demonstrates that sIgM signaling results in activation of some components the UPR in CLL cells. Modulation of the UPR may contribute to variable clinical behavior, and its inhibition may contribute to clinical responses to BCR-associated kinase inhibitors.

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Accepted/In Press date: 17 August 2014
e-pub ahead of print date: 28 August 2014
Published date: 13 November 2014
Organisations: Cancer Sciences

Identifiers

Local EPrints ID: 373200
URI: http://eprints.soton.ac.uk/id/eprint/373200
ISSN: 0006-4971
PURE UUID: aaf87aec-0fe3-4d3a-a3b2-96be4e448e29
ORCID for Andrew J. Steele: ORCID iD orcid.org/0000-0003-0667-1596
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

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Date deposited: 12 Jan 2015 12:11
Last modified: 18 Feb 2021 17:16

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Contributors

Author: Sergey Krysov
Author: Vania Coelho
Author: Adam Linley
Author: Marina Sanchez Hidalgo
Author: Matthew Carter
Author: Benjamin Kennedy
Author: Andrew S. Duncombe
Author: Margaret Ashton-Key
Author: Graham Packham ORCID iD

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