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.
People |
ORCID iD |
Sten Jacobsen (Principal Investigator) |
Publications
Loughran S
(2017)
Mbd3/NuRD controls lymphoid cell fate and inhibits tumorigenesis by repressing a B cell transcriptional program
in Journal of Experimental Medicine
Unnikrishnan A
(2017)
Integrative Genomics Identifies the Molecular Basis of Resistance to Azacitidine Therapy in Myelodysplastic Syndromes.
in Cell reports
Mortera-Blanco T
(2017)
SF3B1-initiating mutations in MDS-RSs target lymphomyeloid hematopoietic stem cells.
in Blood
Giustacchini A
(2017)
Single-cell transcriptomics uncovers distinct molecular signatures of stem cells in chronic myeloid leukemia.
in Nature medicine
Riffelmacher T
(2017)
Autophagy-Dependent Generation of Free Fatty Acids Is Critical for Normal Neutrophil Differentiation.
in Immunity
Mead AJ
(2017)
Niche-mediated depletion of the normal hematopoietic stem cell reservoir by Flt3-ITD-induced myeloproliferation.
in The Journal of experimental medicine
Booth CAG
(2018)
Origins of ETP leukemia.
in Oncoscience
Neo WH
(2018)
Cell-extrinsic hematopoietic impact of Ezh2 inactivation in fetal liver endothelial cells.
in Blood
Booth CAG
(2018)
Ezh2 and Runx1 Mutations Collaborate to Initiate Lympho-Myeloid Leukemia in Early Thymic Progenitors.
in Cancer cell
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 |