liu.seSearch for publications in DiVA
Change search
ReferencesLink to record
Permanent link

Direct link
B cell receptor signaling suppressor SHP-1 is active in CLL lymph node and peripheral blood
Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
Department of Biomedical Science, Health and Society, Malmö University, Malmö, Sweden.
Department of Immunotechnology, Lund Institute of Technology, Lund University, Lund, Sweden.
Department of Biomedical Science, Health and Society, Malmö University, Malmö, Sweden.
Show others and affiliations
(English)Manuscript (preprint) (Other academic)
Abstract [en]

Protein tyrosine phosphatase SHP-1 expression and activity is downregulated or lost in several leukemias and lymphomas due to DNA promotor hypermethylation, catalytic site mutation or oxidation, or phosphorylation at inhibitory sites, implying a negative role of SHP-1 in development of leukemias/lymphomas. In chronic lymphocytic leukemia (CLL), B cell receptor (BcR) and microenvironment signal levels are important in the pathogenesis. Considering that SHP-1 is a BcR signaling suppressor, we hypothesized that SHP-1 would be down-regulated and/or inactivated in the proliferative center lymph node (LN) cells. We analyzed PTPN6 (SHP-1) gene expression, SHP-1 protein expression and phosphorylation status in matched CD5+/CD19+ peripheral blood (PB) and LN cells from 6 CLL patients, and in comparison, BcR (anti-IgM) in vitro triggered CLL PB cells from 10 patients. Gene expression of PTPN6 was significantly higher in PB compared to LN CLL cells in 50% of the cases. SHP-1 protein expression level and phosphorylation at SHP-1Y536 and SHP-1S591 were, however, equal in PB and LN samples. SHP-1 phosphorylation at Y536 and S591, in PB CLL cells cultured ex vivo was significantly reduced upon BcR engagement in all patient samples. These results indicate that in vivo BcR signaling in CLL is paralyzed.

Keyword [en]
B cell, chronic lymphocytic leukemia, SHP-1, suppressor, tyrosine phosphorylation
National Category
Cell and Molecular Biology Clinical Medicine
Identifiers
URN: urn:nbn:se:liu:diva-124575OAI: oai:DiVA.org:liu-124575DiVA: diva2:900449
Available from: 2016-02-04 Created: 2016-02-04 Last updated: 2016-02-04Bibliographically approved
In thesis
1. Importance of microenvironment and antigen in the regulation of growth and survival of CLL cells
Open this publication in new window or tab >>Importance of microenvironment and antigen in the regulation of growth and survival of CLL cells
2016 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Chronic lymphocytic leukemia (CLL) cells rapidly die when put in culture implying that microenvironmental signals delivered by accessory cells confer CLL cells with a growth advantage. Recent findings show that CLL cells are antigen experienced and antigen binding play a critical role in the pathogenesis of the disease. The overall aim of this thesis was to study the influence of the microenvironment and antigen binding in CLL.

In paper I, we studied the influence of the small redox-regulatory molecule thioredoxin (Trx) on CLL cell survival and proliferation. We found Trx to be highly expressed in CLL lymph nodes (LNs), secreted from stromal cells surrounding proliferating CLL cells in proliferation centers, indicating growth promoting properties. Secreted Trx was also shown to protect CLL cells from apoptosis.

In paper II, oxidized LDL was added to subset #1 CLL cells. However, in contrast to our hypothesis, we could not observe activation and proliferation of CLL cells. Instead subset #1 CLL cells were unresponsive/anergic through the B cell receptor (BcR). This anergic state could however be overcome by “wash out” of bound antigen or addition of toll-like receptor 9 stimulation in some patients.

Gene expression profiles differ between groups of CLL patients and in peripheral blood (PB) and LN compartment, due to different microenvironments. However, it is not known whether these differences also apply for DNA methylation. In paper III, we identified various genes that were alternatively methylated between IGHV mutated (M) and unmutated (UM) groups. For example prognostic genes, CLLU1 and LPL, genes involved in B cell signaling, IBTK, as well as numerous TGF-β and NF-κB/TNF pathway genes.

The intensity and duration of BcR signals are fine-tuned by enhancing or inhibitory coreceptors. SHP-1 inhibits BcR-signals by dephosphorylation. In paper IV, we compared the expression and activity of SHP-1 in CLL cells from LN with matched PB samples. However, in contrast to our hypothesis, SHP-1 activity/phosphorylation status in PB and LN, did not differ significantly.

This thesis, add another piece to the puzzle, on how the microenvironment and antigens influence CLL pathogenesis. Since great variations among individuals are seen, further studies in different groups of patients are necessary to elucidate the importance of antigen for the development of CLL.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2016. 83 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1501
National Category
Cell and Molecular Biology Clinical Medicine
Identifiers
urn:nbn:se:liu:diva-124576 (URN)10.3384/diss.diva-124576 (DOI)978-91-7685-867-7 (Print) (ISBN)
Public defence
2016-02-26, Berzeliussalen, Campus US, Linköping, 09:00 (English)
Opponent
Supervisors
Available from: 2016-02-04 Created: 2016-02-04 Last updated: 2016-02-04Bibliographically approved

Open Access in DiVA

No full text

Search in DiVA

By author/editor
Bergh, Ann-CharlotteRosén, Anders
By organisation
Division of Cell BiologyFaculty of Medicine and Health Sciences
Cell and Molecular BiologyClinical Medicine

Search outside of DiVA

GoogleGoogle Scholar
The number of downloads is the sum of all downloads of full texts. It may include eg previous versions that are now no longer available

Total: 207 hits
ReferencesLink to record
Permanent link

Direct link