eprintid: 35870
rev_number: 13
eprint_status: archive
userid: 8676
dir: disk0/00/03/58/70
datestamp: 2025-02-06 10:32:31
lastmod: 2025-02-18 15:40:16
status_changed: 2025-02-06 10:32:31
type: doctoralThesis
metadata_visibility: show
creators_name: Persicke, Michael Rudi Otto
title: The Role of the Inositol Phosphatase SHIP1 in B-Cell Receptor Signalling and CLL Cell Adhesion
subjects: ddc-570
divisions: i-140001
adv_faculty: af-14
abstract: Chronic lymphocytic leukaemia (CLL) is a mature B-cell malignancy with accumulating B-cells in the peripheral blood and secondary lymphoid tissue. CLL cell proliferation is highly dependent on B-cell receptor (BCR) signalling and microenvironmental support. BCR pathway-activated genes are most prominently expressed in CLL cells in lymphatic tissue. Lymphatic tissue is at the same time the major site of CLL cell proliferation. The crucial signalling node of the BCR pathway is PI3K. PI3K activity is countered by the inositol phosphatases Phosphatidylinositol 3,4,5-trisphosphate 3-phosphatase and dual-specificity protein phosphatase PTEN (PTEN) and Src homology domain 2-containing inositol-5′-phosphatase 1 (SHIP1). PTEN reverses PI3K activity by enzymatically converting PIP3 to PI(4,5)P2. In contrast, SHIP1 catalyses the removal of another phosphate residue, thereby degrading PIP3 to phosphatidylinositol-3,4-bisphosphate.
Based on the analysis of a developed model to depict interconnections between signalling factors and to predict beneficial combination treatments, further regulating signalling factors were included in a panel of BCR stimulation dynamics. Through the present work, the impact of PTEN and SHIP1 on stimulation-dependent BCR signalling in CLL and on the adhesion capacity of CLL cells to cells of the microenvironment were investigated. As CLL cells accumulate in two distinct niches in the patients, the fractions of distinct adhesion capacity were separated in flow cytometry measurements and microscopically imaged in a modified and CLL-optimised adhesion under flow assay.
The results of this work indicate that PTEN and SHIP1 control BCR signalling in distinct stimulation conditions. SHIP1 could be shown to be highly relevant in determining the (re-)adhesion capacity of peripheral CLL cells. Furthermore, the von-Hippel Lindau factor was observed to regulate the adhesion of CLL cells and directed future work towards integrins on the CLL cell surface.
Taken together, the present work sheds light on the potential of SHIP1 and related factors as targets for future combination treatment approaches.
date: 2025
id_scheme: DOI
id_number: 10.11588/heidok.00035870
ppn_swb: 1917512996
own_urn: urn:nbn:de:bsz:16-heidok-358701
date_accepted: 2024-05-08
advisor: HASH(0x55e83b1c8b98)
language: eng
bibsort: PERSICKEMITHEROLEOFT20240508
full_text_status: public
place_of_pub: Heidelberg
citation:   Persicke, Michael Rudi Otto  (2025) The Role of the Inositol Phosphatase SHIP1 in B-Cell Receptor Signalling and CLL Cell Adhesion.  [Dissertation]     
document_url: https://archiv.ub.uni-heidelberg.de/volltextserver/35870/1/PhDThesis_MichaelPersicke_a.pdf