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Fernando Dos Anjos Afonso

Dr Fernando Dos Anjos Afonso

Teams and roles for Fernando Dos Anjos Afonso

  • Lecturer

    School of Biosciences

Overview

Research overview

The regulation of normal and malignant haematopoiesis has been substantially elucidated based on valuable mouse genetic studies, however there is a growing appreciation of species-specific differences. With the delineation of the human haematopoietic hierarchy, as a result of recent improvements in the characterization of different haematopoietic stem/progenitor sub-populations, the investigation of human haematopoiesis is now more feasible than before. Therefore, the study of human biology is of the utmost importance for developing therapeutics.

The standard treatment of acute myeloid leukaemia (AML) has changed little in the last three decades and few novel agents have been successfully developed. Despite an initially high complete response rate, many patients relapse and die of their disease. Furthermore, many patients tolerate the intensive chemotherapy poorly due to its toxic and unspecific effects. A large body of experimental work predicts that leukaemic-initiating cells (LICs) may be responsible for the post-treatment relapse and chemoresistance. As with normal human haematopoietic stem cells (HSCs), little is known of the molecular regulation that governs the self-renewal, differentiation and survival of human AML LICs, although both of these cell types share the properties of slow division and self-renewal ability. However, LICs generally have abnormal apoptotic responses or have evolved mechanisms to escape apoptosis. Therefore, the LIC should be the ultimate cellular target to cure human AML. To eradicate AML without killing normal HSCs, it is critical to isolate a target that is expressed or functions specifically at the LIC stage, or to identify a signalling pathway that, when targeted, has a neutral or beneficial effect on normal cells while being harmful to AML LICs.

The latter strategy will be the main focus of the Haematopoietic Signalling group, in which the Notch and other signalling pathways will be explored (human HSC vs LIC biology) as a therapeutic target for AML.

Publication

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Articles

Research

Haematopoietic stem and progenitor cells (HSCs and HPCs) maintain homeostasis of the blood system from day to day by producing a balanced array of progenies. Studies on signalling pathways that govern HSC self-renewal and fate decisions are critical to understand how this occurs and how this balance is skewed during disease formation such as leukaemia. The molecular mechanisms, in particular the cell-to-cell interactions that support and regulate HSCs in their microenvironment are still largely unexplored. Even less is known how these interactions occur in acute myeloid leukaemia (AML), in particular in the leukaemic initiating cell (LIC) compartment that is thought to drive and may be responsible for the post-treatment relapse and chemoresistance of this disease. HSC and LIC share a number of functional features and transcriptional programme but there are also critical differences that can be exploited therapeutically.

Notch signalling is in many ways an ideal candidate pathway for instructing communication between HSCs and their microenvironment (niche), as it requires cell-to-cell contact for activation and is known to play a role in cell fate determination in different stem cell systems. Many gain-of-function studies have shown that activating the Notch pathway results in an increase in HSCs and HPCs, whereas Notch inhibition leads to accelerated differentiation. Early loss-of-function studies in mice did not demonstrate a role for the canonical Notch pathway in the maintenance of adult HSCs. However, very recent data has challenged these early studies and suggests that Notch signalling is important in the haematopoietic compartment to control myeloid progenitor commitment, and the effect may be in part mediated through stromal niche cells in a non–cell-autonomous manner. The importance of Notch signalling in the regulation of adult mouse HSCs/HPCs and their fate decisions is still unresolved. In human cells, Notch signalling has been mainly exploited as a means to expand HSCs/HPCs in vitro but little is known how this pathway is activated or controlled in vivo. The role of the Notch pathway in regulating human HSCs is still largely unexplored and no loss-of function studies have been performed. Thus, our group will address this gap, which will increase our understanding of how Notch signalling regulates human HSC fate decisions and inform future studies of disease.

Notch mutations are rare in AML and little has been described of the role of Notch in this disease. Further to this, Notch signalling appears to be very low in AML despite high expression of Notch receptors on leukaemic cells. Alternative splicing of NOTCH2 receptor is also frequent in primary AML samples, and an increase in the abundance of repressive marks in different Notch target gene promoters has also been observed. Thus, it appears that AML has evolved mechanisms to silence Notch signalling, but how this operates is not well defined. Most importantly, when artificially activating this pathway it leads to apoptosis in AML. However, overt Notch activation in normal human HSCs/HPCs also leads to cell death. Therefore, it would be important to define the optimum Notch activation that has a therapeutic effect in primary human AML samples in vivo, while sparing the functions of normal haematopoiesis. The second focus of our group will be to investigate how AML evades Notch signals as an additional mechanism to escape apoptosis. This fresh view might lead to important clues on how to improve therapeutic outcomes for AML patients by targeting (activating) the Notch pathway.

Current grant support

Active grants as lead applicant

  • BBSRC (2029-2022) - Uncovering the most primitive human blood stem cell population and it's role in regeneration
  • Hodge Foundation (2021-2023) - Gaining a better understanding of how blood stem cells function, so we can improve blood stem cell transplants for patients
  • UK Research & Innovation (2021) - UKRI-COA Uncovering the most primitive human blood stem cell population and it's role in regeneration

Postgraduate research students

Biography

-BSc. (Honours) in Biology (Cell Biology), University of Coimbra, Portugal

-MSc. in Immunology, King’s College, UK

-PhD. in Molecular Immunology, Cancer Research UK (CRUK)/ Institute Child of Health (ICH), University College London, UK

-Post-Doc, Cancer Research UK (CRUK), UK

-Associate Scientist,  Cancer Research UK (CRUK)/The Francis Crick Institute, UK

-Junior Group Leader/Research Fellow, European Cancer Stem Cell Research Institute (ECSCRI), Cardiff University, UK

Contact Details

Email DosAnjosAfonsoF@cardiff.ac.uk
Telephone +44 29206 88511
Campuses Hadyn Ellis Building, Room European Cancer Stem Cell Research Institute, Maindy Road, Cardiff, CF24 4HQ
Breakthrough in blood stem cell research

Breakthrough in blood stem cell research

18 April 2022

Jane Hodge fellow starts new research programme

Jane Hodge fellow starts new research programme

22 October 2015

External profiles