Dr Fernando Dos Anjos Afonso

Lecturer

Ysgol y Biowyddorau

: DosAnjosAfonsoF@caerdydd.ac.uk
: +44 29206 88511
: Adeilad Hadyn Ellis, Ystafell European Cancer Stem Cell Research Institute, Heol Maendy, Caerdydd, CF24 4HQ

Trosolwg ymchwil

Mae rheoleiddio haematopoiesis normal a malaen wedi'i egluro'n sylweddol yn seiliedig ar astudiaethau genetig llygoden gwerthfawr, ond mae gwerthfawrogiad cynyddol o wahaniaethau sy'n benodol i rywogaethau. Gyda dadansoddiad yr hierarchaeth haematopoietig dynol, o ganlyniad i welliannau diweddar yn nodweddu gwahanol is-boblogaethau coesyn / progenitor haematopoietic, mae ymchwilio i haematopoiesis dynol bellach yn fwy ymarferol nag o'r blaen. Felly, mae astudio bioleg ddynol o'r pwys mwyaf ar gyfer datblygu therapiwteg.

Nid yw'r driniaeth safonol o lewcemia myeloid acíwt (AML) wedi newid fawr ddim yn ystod y tri degawd diwethaf ac ychydig o asiantau newydd sydd wedi'u datblygu'n llwyddiannus. Er gwaethaf cyfradd ymateb cyflawn uchel i ddechrau, mae llawer o gleifion yn ymlacio ac yn marw o'u clefyd. Ar ben hynny, mae llawer o gleifion yn goddef y cemotherapi dwys yn wael oherwydd ei effeithiau gwenwynig ac amhenodol. Mae corff mawr o waith arbrofol yn rhagweld y gallai celloedd cychwyn lewcemia (LICs) fod yn gyfrifol am yr ailwaeliad ar ôl triniaeth a chemoresistance. Fel gyda bôn-gelloedd haematopoietig dynol arferol (HSCs), ychydig a wyddys am y rheoliad moleciwlaidd sy'n rheoli hunan-adnewyddu, gwahaniaethu a goroesi AML LICs dynol, er bod y ddau fath hyn o gelloedd yn rhannu priodweddau rhaniad araf a gallu hunan-adnewyddu. Fodd bynnag, yn gyffredinol mae gan LICs ymatebion apoptotig annormal neu maent wedi esblygu mecanweithiau i ddianc rhag apoptosis. Felly, dylai'r LIC fod y targed cellog yn y pen draw i wella AML dynol. Er mwyn dileu AML heb ladd HSCs arferol, mae'n hanfodol ynysu targed sy'n cael ei fynegi neu'n gweithredu'n benodol ar y cam LIG, neu nodi llwybr signalau sydd, o'i dargedu, yn cael effaith niwtral neu fuddiol ar gelloedd normal wrth fod yn niweidiol i AML LICs.

Y strategaeth olaf fydd prif ffocws y grŵp Signalau Haematopoietig, lle bydd y Notch a llwybrau signalau eraill yn cael eu harchwilio (bioleg HSC dynol vs LIG) fel targed therapiwtig ar gyfer AML.

Date
Type

2017

Helft, J., Anjos-Afonso, F., van der Veen, A. G., Chakravarty, P., Bonnet, D. and Reis e Sousa, C. 2017. Dendritic cell lineage potential in human early hematopoietic progenitors. Cell Reports 20(3), pp. 529-537. (10.1016/j.celrep.2017.06.075)
Lampreia, F. P., Carmelo, J. G. and Anjos-Afonso, F. 2017. Notch signaling in the regulation of hematopoietic stem cell. Current Stem Cell Reports (10.1007/s40778-017-0090-8)

2016

Anjos-Afonso, F. et al. 2016. Perturbed hematopoiesis in mice lacking ATMIN. Blood 128(16), pp. 2017-2021. (10.1182/blood-2015-09-672980)
Griessinger, E. et al. 2016. Frequency and dynamics of leukemia-initiating cells during short-term ex vivo culture informs outcomes in acute myeloid leukemia patients. Cancer Research 76(8), pp. 2082-2086. (10.1158/0008-5472.CAN-15-2063)

2015

Foster, K., Lassailly, F., Anjos-Afonso, F., Currie, E., Rouault-Pierre, K. and Bonnet, D. 2015. Different motile behaviors of human hematopoietic stem versus progenitor cells at the osteoblastic niche. Stem Cell Reports 5(5), pp. 690-701. (10.1016/j.stemcr.2015.09.003)
Miraki-Moud, F. et al. 2015. Arginine deprivation using pegylated arginine deiminase has activity against primary acute myeloid leukemia cells in vivo. Blood 125(26), pp. 4060-4068. (10.1182/blood-2014-10-608133)
Costello, P., Sargent, M., Maurice, D., Esnault, C., Foster, K., Anjos-Afonso, F. and Treisman, R. 2015. MRTF-SRF signaling is required for seeding of HSC/Ps in bone marrow during development. Blood 125(8), pp. 1244-1255. (10.1182/blood-2014-08-595603)
Niavarani, A. et al. 2015. APOBEC3A is implicated in a novel class of G-to-A mRNA editing in WT1 transcripts. PLoS ONE 10(3), article number: e0120089. (10.1371/journal.pone.0120089)

2014

Pizzitola, I. et al. 2014. Chimeric antigen receptors against CD33/CD123 antigens efficiently target primary acute myeloid leukemia cells in vivo. Leukemia 28, pp. 1596-1605. (10.1038/leu.2014.62)
Griessinger, E. et al. 2014. A niche-like culture system allowing the maintenance of primary human acute myeloid leukemia-initiating cells: A new tool to decipher their chemoresistance and self-renewal mechanisms. Stem Cells Translational Medicine 3(4), pp. 520-529. (10.5966/sctm.2013-0166)
Anjos-Afonso, F. and Bonnet, D. 2014. Forgotten gems. Cell Cycle 13(4), pp. 503-504. (10.4161/cc.27788)

2013

Anjos-Afonso, F., Currie, E., Palmer, H., Foster, K., Taussig, D. and Bonnet, D. 2013. CD34− cells at the apex of the human hematopoietic stem cell hierarchy have distinctive cellular and molecular signatures. Cell Stem Cell 13(2), pp. 161-174. (10.1016/j.stem.2013.05.025)
Rouault-Pierre, K. et al. 2013. HIF-2α protects human hematopoietic stem/progenitors and acute myeloid leukemic cells from apoptosis induced by endoplasmic reticulum stress. Cell Stem Cell 13(5), pp. 549-563. (10.1016/j.stem.2013.08.011)
Jaganathan, B., Anjos-Afonso, F., Kumar, A. and Bonnet, D. 2013. Active RHOA favors retention of human hematopoietic stem/progenitor cells in their niche. Journal of Biomedical Science 20(1), article number: 66. (10.1186/1423-0127-20-66)
Miraki-Moud, F. et al. 2013. Acute myeloid leukemia does not deplete normal hematopoietic stem cells but induces cytopenias by impeding their differentiation. Proceedings of the National Academy of Sciences of the United States of America 110(33), pp. 13576-13581. (10.1073/pnas.1301891110)

2012

Kallinikou, K. et al. 2012. Engraftment defect of cytokine-cultured adult human mobilized CD34+ cells is related to reduced adhesion to bone marrow niche elements. British Journal of Haematology 158(6), pp. 778-787. (10.1111/j.1365-2141.2012.09219.x)

2011

Anjos-Afonso, F. and Bonnet, D. 2011. Prospective identification and isolation of murine bone marrow derived multipotent mesenchymal progenitor cells. Best Practice & Research Clinical Haematology 24(1), pp. 13-24. (10.1016/j.beha.2010.11.003)
Vargaftig, J. et al. 2011. Frequency of leukemic initiating cells does not depend on the xenotransplantation model used. Leukemia 26(4), pp. 858-860. (10.1038/leu.2011.250)

2010

Poulin, L. F. et al. 2010. Characterization of human DNGR-1+ BDCA3+ leukocytes as putative equivalents of mouse CD8 + dendritic cells. Journal of Experimental Medicine 207(6), pp. 1261-1271. (10.1084/jem.20092618)

2008

Anjos-Afonso, F. and Bonnet, D. 2008. Isolation, culture, and differentiation potential of mouse marrow stromal cells. Current Protocols in Stem Cell Biology (10.1002/9780470151808.sc02b03s7)
Pálmer, H. G., Anjos-Afonso, F., Carmeliet, G., Takeda, H. and Watt, F. M. 2008. The vitamin D receptor is a Wnt effector that controls hair follicle differentiation and specifies tumor type in adult epidermis. PLoS ONE 3(1), article number: e1483. (10.1371/journal.pone.0001483)
Taussig, D. C. et al. 2008. Anti-CD38 antibody-mediated clearance of human repopulating cells masks the heterogeneity of leukemia-initiating cells. Blood -New York- 112(3), pp. 568-575. (10.1182/blood-2007-10-118331)

2007

Pearce, D. J., Anjos-Afonso, F., Ridler, C. M., Eddaoudi, A. and Bonnet, D. 2007. Age-dependent increase in side population distribution within hematopoiesis: implications for our understanding of the mechanism of aging. Stem Cells 25(7), pp. 1852. (10.1634/stemcells.2006-0405erratum)
Anjos-Afonso, F. and Bonnet, D. 2007. Flexible and dynamic organization of bone marrow stromal compartment. British Journal of Haematology 139(3), pp. 373-384. (10.1111/j.1365-2141.2007.06827.x)
Pearce, D. J., Anjos-Afonso, F., Ridler, C. M., Eddaoudi, A. and Bonnet, D. 2007. Age-dependent increase in side population distribution within hematopoiesis: Implications for our understanding of the mechanism of aging. Stem Cells 25(4), pp. 828-835. (10.1634/stemcells.2006-0405)

2006

Anjos-Afonso, F. and Bonnet, D. 2006. Nonhematopoietic/endothelial SSEA-1+ cells define the most primitive progenitors in the adult murine bone marrow mesenchymal compartment. Blood 109(3), pp. 1298-1306. (10.1182/blood-2006-06-030551)

2004

Anjos-Afonso, F., Siapati, E. K. and Bonnet, D. 2004. In vivo contribution of murine mesenchymal stem cells into multiple cell-types under minimal damage conditions. Journal of Cell Science 117(23), pp. 5655-5664. (10.1242/jcs.01488)

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.

Postgraduate research students

Mr Fabio Lampreia

-BSc. (Anrhydedd) mewn Bioleg (Bioleg Celloedd), Prifysgol Coimbra, Portiwgal

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

-PhD. mewn Imiwnoleg Moleciwlaidd, Ymchwil Canser y DU (CRUK) / Sefydliad Plant Iechyd (ICH), Coleg Prifysgol Llundain, UK

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

-Gwyddonydd Cyswllt, Ymchwil Canser y DU (CRUK)/The Francis Crick Institute, UK

-Arweinydd/Cymrawd Ymchwil Grŵp Iau, Sefydliad Ymchwil Bôn-gelloedd Canser Ewrop (ECSCRI), Prifysgol Caerdydd, UK

Datblygiad arloesol mewn ymchwil i fôn-gelloedd y gwaed

18 April 2022

Cymrawd Jane Hodge yn cychwyn rhaglen ymchwil newydd

22 October 2015

External profiles

ORCID

Dr Fernando Dos Anjos Afonso

Trosolwyg

Trosolwg ymchwil

Cyhoeddiad

2023

2022

2021

2020

2018