Understanding cell fate decisions in normal and abnormal haematopoiesis

Lead Research Organisation: University of Oxford

Abstract

The research programme in the Jacobsen laboratory aims to improve our understanding of how development of the different blood cell lineages occurs from blood forming stem cells in the adult bone marrow and in the embryo. A main focus is to understand the molecular regulation of these processes with the goal of identifying pathways which can be used to enhanced regeneration of specific blood lineages in clinical settings. Another main focus is to understand how the blood forming stem and progenitor cells as well as key signalling pathways regulating them, are perturbed in leukaemia and other haematological malignancies, with the goal of identifying new therapeutic targets at the cellular and molecular level. These research questions will be pursued in mouse models of normal and leukaemic haematopoiesis, as well as through studies of normal and leukaemic stem cells from human subjects.

Technical Summary

The research in the Jacobsen laboratory will remain focussed at obtaining a better understanding of the cellular pathways of normal lineage commitment from multipotent HSCs to lineage-restricted progenitors. However, in the coming years, while devoting an increasing emphasis on unravelling the molecular determinants of the now established lineage commitment steps in the earliest stages of lympho-myelopoiesis in adult haematopoiesis, an increasing effort will be devoted towards identifying and characterising the earliest stages of lineage commitment in the embryo. Furthermore, with an increasing understanding of lineage commitment steps in normal haematopoiesis, the Jacobsen laboratory will with support of the strong mouse genetics efforts within the MHU, embark on new research lines, in which the goal is to understand the impact of distinct pre-leukaemic and leukaemic mutations on distinct stages of lineage commitment. Finally, the laboratory will continue their efforts to uncover the cellular and molecular determinants of the haematopoietic defects in MDS, and its transformation to AML.

Publications

10 25 50
 
Description Chairman of Committee for allogeneic transplantations and cell therapies, Karolinska University Hospital
Geographic Reach National 
Policy Influence Type Membership of a guideline committee
Impact Allogeneic transplantations and cell therapies.
 
Description International Society for Stem Cell Research (ISSCR) McEwen Award for Innovation selection committee
Geographic Reach Europe 
Policy Influence Type Membership of a guideline committee
Impact International Society for Stem Cell Research (ISSCR) McEwen Award for Innovation selection committee
URL http://www.isscr.org
 
Description Member of Board of Center for Molecular Medicine, Karolinska Institutet
Geographic Reach National 
Policy Influence Type Membership of a guideline committee
Impact Member of Board of Center for Molecular Medicine, Karolinska Institutet
 
Description Member of Board of Center of Excellence in Developmental Biology, Karolinska Institute
Geographic Reach National 
Policy Influence Type Membership of a guideline committee
Impact Member of Board of Center of Excellence in Developmental Biology, Karolinska Institute (Director, Professor Urban Lendahl)
 
Description Member of Scientific Advisory Board, Stem Cell Institute, Leuven, Belgium
Geographic Reach National 
Policy Influence Type Participation in a advisory committee
Impact Member of Scientific Advisory Board, Stem Cell Institute, Leuven, Belgium (Director Professor Catherine Verfaillie) - Starting date 2005-date
URL http://www.kuleuven.be/samenwerking/scil
 
Description Permanent member of Cell and Developmental Biology Expert Review Group, Wellcome Trust
Geographic Reach Europe 
Policy Influence Type Participation in a advisory committee
 
Description Acquisition of high-end FACS cell sorter for WIMM FACS facility.
Amount £50,000 (GBP)
Organisation University of Oxford 
Department John Fell Fund
Sector Academic/University
Country United Kingdom
Start 01/2014 
End 12/2014
 
Description Characterisation and regulation of distinct hematopoietic stem and progenitor cells
Amount £800,000 (GBP)
Organisation Medical Research Council (MRC) 
Department MRC Molecular Haematology Unit
Sector Public
Country United Kingdom
Start 04/2012 
End 03/2017
 
Description Characterization of the platelet-biased haematopoietic stem cells niche in homeostasis and after acute platelet depletion
Amount £268,015 (GBP)
Funding ID KKL832 
Organisation The Kay Kendall Leukaemia Fund 
Sector Charity/Non Profit
Country United Kingdom
Start 07/2014 
End 06/2018
 
Description Establishment of Hematopoietic Stem Cell Research Program at the Karolinska Institute
Amount 93,000,000 kr (SEK)
Organisation Swedish Research Council 
Sector Public
Country Switzerland
Start  
 
Description Impact of Leukaemia-Associated Loss of Function Epigenetic Regulators on Distinct Haematopoietic Stem Cells
Amount £266,517 (GBP)
Funding ID KKL1102 
Organisation The Kay Kendall Leukaemia Fund 
Sector Charity/Non Profit
Country United Kingdom
Start 01/2017 
End 12/2020
 
Description Professor/ Prize in Medicine 2015
Amount 10,000,000 kr (SEK)
Organisation Torsten Söderberg Foundation 
Sector Academic/University
Country Sweden
Start 01/2016 
End 12/2025
 
Description The identification of small molecule agents that can induce selective differentiation of cancer stem like cells (CSLSs) to more benign states leading to anti-tumour activity in vivo
Amount £3,118,483 (GBP)
Funding ID R39746/CN001 
Organisation Oxstem Limited 
Start 05/2016 
End 05/2019
 
Description Tobias Award
Amount 10,000,000 kr (SEK)
Organisation Tobias Foundation 
Sector Private
Country Sweden
Start  
 
Description Unravelling the biology of embryonic lymphomyeloid progenitors and llineage-biased haematopoietic stem cells. Stem-progenitor cell biology in unperturbed haematopoiesis
Amount £27,659,000 (GBP)
Funding ID MC_UU_12009/5 
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 04/2017 
End 03/2020
 
Description Unravelling the molecular and therapeutic targets in single del(5q) MDS stem and progenitor cells
Amount £249,464 (GBP)
Funding ID 17017 
Organisation Bloodwise 
Sector Charity/Non Profit
Country United Kingdom
Start 01/2018 
End 12/2019
 
Title A new mouse model for identification of Hematopoietic stem cells. 
Description Generation of new mouse models for identification of Hematopoietic stem cells (Sanjuan-Pla A et al. Platelet-biased stem cells reside at the apex of the haematopoietic stem-cell hierarchy. Nature 2013 Oct 10;502(7470):232-6 and Carrelha et al, Nature 2018) 
Type Of Material Model of mechanisms or symptoms - in vitro 
Year Produced 2018 
Provided To Others? Yes  
Impact Distributed to and used by many research groups for studies if hematopoietic stem cells 
 
Description Adam Mead 
Organisation University of Oxford
Department Weatherall Institute of Molecular Medicine (WIMM)
Country United Kingdom 
Sector Public 
PI Contribution Mouse models of normal and malignant hematopoiesis
Collaborator Contribution Molecular analysis of hematopoiesis
Impact Multiple publications listed in outcome
Start Year 2008
 
Description Andrew Smith 
Organisation University of Oxford
Department Weatherall Institute of Molecular Medicine (WIMM)
Country United Kingdom 
Sector Public 
PI Contribution -
Collaborator Contribution -
Impact -
Start Year 2010
 
Description Anna Katharina (Katja) Simon 
Organisation University of Oxford
Department Weatherall Institute of Molecular Medicine (WIMM)
Country United Kingdom 
Sector Public 
PI Contribution -
Collaborator Contribution -
Impact -
Start Year 2006
 
Description Anthony (Tony) Green 
Organisation University of Cambridge
Department Cambridge Institute for Medical Research (CIMR)
Country United Kingdom 
Sector Academic/University 
PI Contribution -
Collaborator Contribution -
Impact -
Start Year 2006
 
Description Claus Nerlov 
Organisation University of Oxford
Department Weatherall Institute of Molecular Medicine (WIMM)
Country United Kingdom 
Sector Public 
PI Contribution stem and progenitor cell characterisation
Collaborator Contribution Mouse genetic models of normal and malignant hematopoiesis
Impact As listed in outcome multiple high impact joint publications
Start Year 2006
 
Description Elli Papaemmanuil 
Organisation The Wellcome Trust Sanger Institute
Country United Kingdom 
Sector Charity/Non Profit 
PI Contribution MDS stem cells for sequencing for targeted mutations
Collaborator Contribution Expertise in exome sequencing
Impact Key for publication Woll et al, Cancer Cell, 2014
Start Year 2010
 
Description Geissmann F. 
Organisation Lund University
Country Sweden 
Sector Academic/University 
PI Contribution -
Collaborator Contribution -
Impact -
 
Description Marella de Bruijn 
Organisation University of Oxford
Department Weatherall Institute of Molecular Medicine (WIMM)
Country United Kingdom 
Sector Public 
PI Contribution Mouse Models for stem and progenitor biology
Collaborator Contribution Expertise in mouse developmental hematopoiesis
Impact Several publications, including Boiers et al, Cell Stem Cell 2013 and Luc et al, Nature Immunology 2012
Start Year 2010
 
Description Paresh Vyas 
Organisation University of Oxford
Department Weatherall Institute of Molecular Medicine (WIMM)
Country United Kingdom 
Sector Public 
PI Contribution Mouse models of MDS and malignant hematopoiesis
Collaborator Contribution Clinical expertise in MDS and AML
Impact Several publications including Goardon et al, Cancer Cell 2010; Tehranchi et al, NEJM 2010; Woll et al, Cancer Cell 2014
Start Year 2008
 
Description Peter Campbell 
Organisation The Wellcome Trust Sanger Institute
Country United Kingdom 
Sector Charity/Non Profit 
PI Contribution -
Collaborator Contribution -
Impact -
Start Year 2006
 
Description Professor Stephen G. Davies 
Organisation University of Oxford
Country United Kingdom 
Sector Academic/University 
PI Contribution Models and assays for cancer/MDS stem cell targeting
Collaborator Contribution chemical libraries for targeting of MDS stem cells
Impact -Estabishment of spin-off company OxStem Oncology
Start Year 2014
 
Description Rickard Sandberg 
Organisation Lund University
Country Sweden 
Sector Academic/University 
PI Contribution -
Collaborator Contribution -
Impact -
Start Year 2006
 
Description Sten Linnarsson 
Organisation Karolinska Institute
Country Sweden 
Sector Academic/University 
PI Contribution Single cell analysis of stem and progenitor cells
Collaborator Contribution Sten Linnarsson is a world leader in single cell RNA sequencing and his input has been key to several of our reported publications utilising small cell number or single cell RNA sequencing (Cell Stem Cell 2013; Cancer Cell 2014)
Impact Publications as listed above
Start Year 2011
 
Description Thomas Milne 
Organisation University of Oxford
Department Weatherall Institute of Molecular Medicine (WIMM)
Country United Kingdom 
Sector Public 
PI Contribution -
Collaborator Contribution -
Impact -
Start Year 2010
 
Company Name OX Stem Oncology 
Description Establishment (as co-founder) of a spin-off company for development of targeting of cancer stem cells. 
Year Established 2016 
Impact Development of therapeutic targeting of cancer stem cells.