Dissecting the effects of acute myeloid leukaemia and chemotherapy on haematopoietic stem cells and their niche: on the road to haematopoietic recovery.
File(s)
Author(s)
Gonzalez Anton, Sara
Type
Thesis
Abstract
Haematopoietic stem cells (HSC) are a rare and essential blood cell population that maintains haematopoiesis throughout the lifespan of an organism. HSC function, differentiation and dynamics are highly regulated by the bone marrow microenvironment in which they reside. This HSC BM niche is formed by several haematopoietic, stromal cells and extracellular matrix. Acute myeloid leukaemia (AML) is an aggressive type of blood cancer with poor prognosis, and it has been shown to damage not only the haematopoietic system but also the BM niche. The main treatment for AML consists of several cycles of chemotherapy followed up, when possible, by a stem cell transplantation. Despite the need of chemotherapy to reduce the burden of the disease, this treatment is a double edge sword as it is also highly toxic. The detrimental effect of chemotherapy on the BM niche leads to a slow recovery of the patients, increasing the risk of infections and generating different long-term side effects on the patients that survive.
Using a murine model of AML, treated with a cycle of Doxorubicin and Cytarabine, I could study the effects of AML and chemotherapy on the HSC niche. Using a variety of niche reporter mice and immunostainings we observed disruption of the perivascular niche. Vasculature and mesenchymal stem/stromal cells are disrupted by both, AML and chemotherapy, and factors that are essential for the maintenance of HSCs and recovery after injury are significantly decreased. We identified three potential factors that are disrupted by AML and can be potentially interesting therapeutic targets to improve chemotherapy efficacy and enhance haematopoietic recovery: FGF-1, adiponectin and PDGFB.
These results highlight the need to increase our understanding on how AML and chemotherapy hamper haematopoietic and stromal recovery. This will allow us to find new and more specific targets to recover these populations and improve patient recovery.
Using a murine model of AML, treated with a cycle of Doxorubicin and Cytarabine, I could study the effects of AML and chemotherapy on the HSC niche. Using a variety of niche reporter mice and immunostainings we observed disruption of the perivascular niche. Vasculature and mesenchymal stem/stromal cells are disrupted by both, AML and chemotherapy, and factors that are essential for the maintenance of HSCs and recovery after injury are significantly decreased. We identified three potential factors that are disrupted by AML and can be potentially interesting therapeutic targets to improve chemotherapy efficacy and enhance haematopoietic recovery: FGF-1, adiponectin and PDGFB.
These results highlight the need to increase our understanding on how AML and chemotherapy hamper haematopoietic and stromal recovery. This will allow us to find new and more specific targets to recover these populations and improve patient recovery.
Version
Open Access
Date Issued
2022-12-23
Date Awarded
01/11/2023
License URL
Advisor
Lo Celso, Cristina
Sponsor
Cancer Research UK
Grant Number
C36195/A26770
Publisher Department
Life Sciences
Publisher Institution
Imperial College London
Qualification Level
Doctoral
Qualification Name
Doctor of Philosophy (PhD)