Understanding cell fate decisions in normal and abnormal haematopoiesis

Lead Research Organisation: University of Oxford
Department Name: UNLISTED

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

publication icon
Booth CAG (2018) Origins of ETP leukemia. in Oncoscience

publication icon
Chaves P (2018) Loss of Canonical Notch Signaling Affects Multiple Steps in NK Cell Development in Mice. in Journal of immunology (Baltimore, Md. : 1950)

publication icon
Czeh M (2022) DNMT1 Deficiency Impacts on Plasmacytoid Dendritic Cells in Homeostasis and Autoimmune Disease. in Journal of immunology (Baltimore, Md. : 1950)

publication icon
Jacobsen SEW (2019) Haematopoiesis in the era of advanced single-cell technologies. in Nature cell biology

Related Projects

Project Reference Relationship Related To Start End Award Value
MC_UU_00016/1 31/03/2017 30/03/2022 £3,035,000
MC_UU_00016/2 Transfer MC_UU_00016/1 31/03/2017 30/03/2022 £3,411,000
MC_UU_00016/3 Transfer MC_UU_00016/2 31/03/2017 30/03/2022 £1,366,000
MC_UU_00016/4 Transfer MC_UU_00016/3 31/03/2017 30/03/2020 £3,017,000
MC_UU_00016/5 Transfer MC_UU_00016/4 31/03/2017 30/03/2020 £497,000
MC_UU_00016/6 Transfer MC_UU_00016/5 31/03/2017 30/03/2022 £2,530,000
MC_UU_00016/7 Transfer MC_UU_00016/6 31/03/2017 30/03/2022 £2,018,000
MC_UU_00016/8 Transfer MC_UU_00016/7 31/03/2017 30/03/2018 £1,131,000
MC_UU_00016/9 Transfer MC_UU_00016/8 31/03/2017 30/03/2022 £2,500,000
MC_UU_00016/10 Transfer MC_UU_00016/9 31/03/2017 30/03/2018 £1,171,000
MC_UU_00016/11 Transfer MC_UU_00016/10 31/03/2017 30/03/2022 £1,387,000
MC_UU_00016/12 Transfer MC_UU_00016/11 31/03/2017 30/03/2022 £446,000
 
Description Member of board for Strategic Research Area of Stem Cells and Regenerative Medicine, Karolinska Institutet, Sweden.
Geographic Reach National 
Policy Influence Type Participation in a guidance/advisory committee
 
Description Permanent member of Cell and Developmental Biology Expert Review Group, Wellcome Trust
Geographic Reach Europe 
Policy Influence Type Participation in a guidance/advisory committee
 
Description Acquisition of high parameter cell sorter, FACSymphony S6 to WIMM FACS Core Facility
Amount £112,500 (GBP)
Funding ID 0008760 
Organisation University of Oxford 
Department John Fell Fund
Sector Academic/University
Country United Kingdom
Start 07/2020 
End 08/2021
 
Description Cellular, molecular and clinical surveillance of clonal hematopoiesis during aging
Amount 6,000,000 kr (SEK)
Organisation Karolinska Institute 
Sector Academic/University
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 Public
Country United Kingdom
Start 03/2017 
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 Academic/University 
PI Contribution Mouse models of normal and malignant hematopoiesis.
Collaborator Contribution Molecular analysis of hematopoiesis.
Impact Multiple high impact publications listed in outcome.
Start Year 2008
 
Description Anna Katharina (Katja) Simon 
Organisation University of Oxford
Department Weatherall Institute of Molecular Medicine (WIMM)
Country United Kingdom 
Sector Academic/University 
PI Contribution Hematopoietic characterization of mice deficient in autophagy pathways.
Collaborator Contribution Mouse models of autophagy deficiency.
Impact Multiple joint high impact publications, see list of publication outputs.
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 Hematopoietic characterization of mouse models of hematological malignancies.
Collaborator Contribution Development and studies of mouse models of hematological malignancies.
Impact Multiple collaborative publications, see publication output.
Start Year 2006
 
Description Claus Nerlov 
Organisation University of Oxford
Department Weatherall Institute of Molecular Medicine (WIMM)
Country United Kingdom 
Sector Academic/University 
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 Johanna Olweus 
Organisation Oslo University Hospital
Country Norway 
Sector Hospitals 
PI Contribution Characterization of leukemic hemaptopiesis and leukemic stem cells in therapeutic models with TCR targeting of acute leukemia
Collaborator Contribution Engineering of TCRs for targeting human leukemia
Impact Joint publication in Nature Biotechnology 2022, see publication output
Start Year 2018
 
Description Marella de Bruijn 
Organisation University of Oxford
Department Weatherall Institute of Molecular Medicine (WIMM)
Country United Kingdom 
Sector Academic/University 
PI Contribution Mouse Models for stem and progenitor biology.
Collaborator Contribution Expertise in mouse developmental hematopoiesis.
Impact Several high impact joint publications, as specified in publication output.
Start Year 2010
 
Description Rickard Sandberg 
Organisation Lund University
Country Sweden 
Sector Academic/University 
PI Contribution Single cell studies of hematopoiesis and stem cells
Collaborator Contribution Single cell rna sequencing expertise and analysis
Impact As seen in publication output list multiple joint high impact publications
Start Year 2006
 
Description Seishi Ogawa 
Organisation University of Kyoto
Country Japan 
Sector Academic/University 
PI Contribution Genetic characterization of stem cells in hematological malignancies.
Collaborator Contribution Expertise in DNA sequencing analysis of hematological malignancies.
Impact Joint publication in Blood 2022, see output publications.
Start Year 2015
 
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 (including Cell Stem Cell 2013; Cancer Cell 2014).
Impact Publications as listed above.
Start Year 2011