Niche disturbances in Chronic Lymphocytic Leukaemia affect HSC residency and drug resistance
type: CreativeWork
description: Chronic lymphocytic leukaemia (CLL) is an indolent B cell malignancy infiltrating the lymphatic system and invariably the bone marrow (BM). Although treatment options for patients with advanced disease have significantly increased in the past years and improved life-expectancies, the disease remains incurable and after emergence of therapy resistant disease patients succumb to infections due to secondary BM failure. Survival of CLL cells depends on protein kinase C- (PKC) expressed in activated BM mesenchymal stromal cells (BM-MSCs) which display activation of inflammatory pathways, as well as BM endothelial cells (BMEC) (Lutzny et al., 2013). This activation provides a nurturing environment, which not only contributes to disease progression, but likely also disrupts normal haematopoiesis, leading to insufficient blood production. I hypothesised that disease-induced alterations in the tumour microenvironment of CLL cells contribute to BM failure by skewing hematopoietic stem and progenitor cell (HSPC) fate choice commitments and tissue residency. In my study, the analysis of the peripheral blood (PB) of 67 patients with predominantly early stage CLL revealed that short term (ST) HSCs and Common Myelo-Erythroid Progenitors (CMP/MEPs) are found in higher frequencies and are associated with a skewed differentiation into myeloid cells in vitro and progenitor cells are less likely to produce erythrocytes. These findings provide evidence for the mechanisms underlying BM failure in patients with CLL. Our current knowledge of how malignant B cells interact with stromal cells within the BM microenvironment is limited. I hypothesised that BMEC play a fundamental role in nurturing malignant B cells during disease progression. In a murine model for CLL, I identified that malignant B cells home preferentially to the BM in close proximity to EC, and during disease progression, sinusoidal, but not arterial vessels, upregulate the stem cell marker, SCA1. RNAseq analyses of the re…
abstract: Chronic lymphocytic leukaemia (CLL) is an indolent B cell malignancy infiltrating the lymphatic system and invariably the bone marrow (BM). Although treatment options for patients with advanced disease have significantly increased in the past years and improved life-expectancies, the disease remains incurable and after emergence of therapy resistant disease patients succumb to infections due to secondary BM failure. Survival of CLL cells depends on protein kinase C- (PKC) expressed in activated BM mesenchymal stromal cells (BM-MSCs) which display activation of inflammatory pathways, as well as BM endothelial cells (BMEC) (Lutzny et al., 2013). This activation provides a nurturing environment, which not only contributes to disease progression, but likely also disrupts normal haematopoiesis, leading to insufficient blood production. I hypothesised that disease-induced alterations in the tumour microenvironment of CLL cells contribute to BM failure by skewing hematopoietic stem and progenitor cell (HSPC) fate choice commitments and tissue residency. In my study, the analysis of the peripheral blood (PB) of 67 patients with predominantly early stage CLL revealed that short term (ST) HSCs and Common Myelo-Erythroid Progenitors (CMP/MEPs) are found in higher frequencies and are associated with a skewed differentiation into myeloid cells in vitro and progenitor cells are less likely to produce erythrocytes. These findings provide evidence for the mechanisms underlying BM failure in patients with CLL. Our current knowledge of how malignant B cells interact with stromal cells within the BM microenvironment is limited. I hypothesised that BMEC play a fundamental role in nurturing malignant B cells during disease progression. In a murine model for CLL, I identified that malignant B cells home preferentially to the BM in close proximity to EC, and during disease progression, sinusoidal, but not arterial vessels, upregulate the stem cell marker, SCA1. RNAseq analyses of the re…
author: Santoro, Antonella
language: eng
keywords: microenvironment, B cell leukemia, haematopoietic stem cells, inflammation, endothelial niche, drug resistance
license: https://apollo8-f-pro.lib.cam.ac.uk/bitstreams/8382d244-b630-4e67-a8b4-ba934d5ceeda/download
license: https://www.rioxx.net/licenses/all-rights-reserved/
date published: 2020-10-29
date modified: 2026-07-22T22:24:24Z
provider: Cambridge University
publisher: Networked Digital Library of Theses and Dissertations
type: WebPage
source organization: University of Cambridge

PropertyValue
property ID: DOI
value: 10.17863/CAM.69539