Cellular mechanisms of haematopoietic lineage commitment
Lead Research Organisation:
University of Oxford
Department Name: UNLISTED
Abstract
This project will analyse individual blood forming cells and the changes they undergo in cancer, during aging and under stress conditions (blood loss, infection) to understand how the body deals with and responds to these challenges.This will be done by using advanced DNA sequencing technology to measure which genes are expressed in each individual cell, and how this pattern changes in the presence of stress hormones, in stem cells that contain mutations that cause leukaemia, and in aged stem cells. The aim is toidentify different types of of blood forming stem cells, andto find outhow these populations change during aging. We will also analyse alsohow stress signals alterthe composition of the hematopoietic stem cell populations and influences their differentiation pattern. This will enable us to design and develop rational therapies to promote or counteract these changes, as required.
Technical Summary
Haematopoiesis has served as a valuable paradigm for how multipotent stem cells are maintained and their differentiation regulated. Thus far elucidation of haematopoietic stem cells and their differentiation, as well as analysis of the alterations they undergo during aging, has generally been hypothesis-driven, enabled by the prospective isolation of discrete cell populations and their functional characterisation. However, recent progress has demonstrated a high degree of complexity of both the haematopoietic stem cell compartment and the pathways by which they form their differentiated progeny, indicating that the current models for how haematopoietic lineage separation are incomplete. With the advent of single cell transcriptome analysis we now have the opportunity to interrogate stem- and progenitor cell populations in a non-biased manner in order to define progenitor populations and their relationships. By combining this technology with novel reporter lines allowing identification of novel stem- and progenitor cell subsets, as well as sensitive readout of erythroid cells and platelets, and the use of lineage tracing, we are now in a position to comprehensively analyse, at the single cell level, the transcriptomes, lineage potentials and cellular relationships within the haematopoietic stem- and progenitor cell compartments. Such studies will allow us to address with a much higher degree of accuracy the impact of aging and oncogenic mutations on the haematopoietic system, and increase our understanding of how immune cell output is modulated by cytokines during microbial insult.
Organisations
People |
ORCID iD |
| Claus Nerlov (Principal Investigator) |
Publications
Mead AJ
(2017)
Niche-mediated depletion of the normal hematopoietic stem cell reservoir by Flt3-ITD-induced myeloproliferation.
in The Journal of experimental medicine
Carrieri C
(2017)
A transit-amplifying population underpins the efficient regenerative capacity of the testis.
in The Journal of experimental medicine
Buono M
(2018)
Bi-directional signaling by membrane-bound KitL induces proliferation and coordinates thymic endothelial cell and thymocyte expansion.
in Nature communications
Pinho S
(2018)
Lineage-Biased Hematopoietic Stem Cells Are Regulated by Distinct Niches.
in Developmental cell
Duarte S
(2018)
Canonical Notch signaling is dispensable for adult steady-state and stress myelo-erythropoiesis.
in Blood
Zriwil A
(2018)
Direct role of FLT3 in regulation of early lymphoid progenitors.
in British journal of haematology
Azzoni E
(2018)
Kit ligand has a critical role in mouse yolk sac and aorta-gonad-mesonephros hematopoiesis.
in EMBO reports
Brown E
(2018)
Multiple membrane extrusion sites drive megakaryocyte migration into bone marrow blood vessels.
in Life science alliance
Reckzeh K
(2018)
Human adult HSCs can be discriminated from lineage-committed HPCs by the expression of endomucin.
in Blood advances
Carrelha J
(2018)
Hierarchically related lineage-restricted fates of multipotent haematopoietic stem cells
in Nature
Braun T
(2019)
Myeloid lineage enhancers drive oncogene synergy in CEBPA/CSF3R mutant acute myeloid leukemia
in Nature Communications
Drissen R
(2019)
Identification of two distinct pathways of human myelopoiesis.
in Science immunology
Jacobsen SEW
(2019)
Haematopoiesis in the era of advanced single-cell technologies.
in Nature cell biology
Schmidt L
(2019)
CEBPA-mutated leukemia is sensitive to genetic and pharmacological targeting of the MLL1 complex.
in Leukemia
Volpe G
(2019)
Dependence on Myb expression is attenuated in myeloid leukaemia with N-terminal CEBPA mutations.
in Life science alliance
Di Genua C
(2019)
Cell-intrinsic depletion of Aml1-ETO-expressing pre-leukemic hematopoietic stem cells by K-Ras activating mutation.
in Haematologica
Lopez CK
(2019)
Ontogenic Changes in Hematopoietic Hierarchy Determine Pediatric Specificity and Disease Phenotype in Fusion Oncogene-Driven Myeloid Leukemia.
in Cancer discovery
Etzrodt M
(2019)
Inflammatory signals directly instruct PU.1 in HSCs via TNF.
in Blood
Mello T
(2020)
Liver haploinsufficiency of RuvBL1 causes hepatic insulin resistance and enhances hepatocellular carcinoma progression.
in International journal of cancer
Rabe JL
(2020)
CD34 and EPCR coordinately enrich functional murine hematopoietic stem cells under normal and inflammatory conditions.
in Experimental hematology
Di Genua C
(2021)
To bi or not to bi: Acute erythroid leukemias and hematopoietic lineage choice.
in Experimental hematology
Kaeppler JR
(2022)
Endothelial cell death after ionizing radiation does not impair vascular structure in mouse tumor models.
in EMBO reports
Czeh M
(2022)
DNMT1 Deficiency Impacts on Plasmacytoid Dendritic Cells in Homeostasis and Autoimmune Disease.
in Journal of immunology (Baltimore, Md. : 1950)
Meng Y
(2023)
Epigenetic programming defines haematopoietic stem cell fate restriction.
in Nature cell biology
Luis TC
(2023)
Perivascular niche cells sense thrombocytopenia and activate hematopoietic stem cells in an IL-1 dependent manner.
in Nature communications
Kaltenbach L
(2023)
Slow integrin-dependent migration organizes networks of tissue-resident mast cells.
in Nature immunology
Fagnan A
(2024)
The ETO2 transcriptional cofactor maintains acute leukemia by driving a MYB/EP300-dependent stemness program.
in HemaSphere
Carrelha J
(2024)
Alternative platelet differentiation pathways initiated by nonhierarchically related hematopoietic stem cells.
in Nature immunology
Gaertner F
(2024)
Plasmacytoid dendritic cells control homeostasis of megakaryopoiesis.
in Nature
Aksöz M
(2024)
Hematopoietic stem cell heterogeneity and age-associated platelet bias are evolutionarily conserved.
in Science immunology
Zhang S
(2024)
Platelet Factor 4 (PF4) Regulates Hematopoietic Stem Cell Aging.
in bioRxiv : the preprint server for biology
Jakobsen NA
(2024)
Selective advantage of mutant stem cells in human clonal hematopoiesis is associated with attenuated response to inflammation and aging.
in Cell stem cell
Toghani D
(2025)
Niche-derived Semaphorin 4A safeguards functional identity of myeloid-biased hematopoietic stem cells.
in Nature aging
| Description | Counteracting hematopoietic ageing by pharmacological inhibition of TGFbeta and IL-6 signaling |
| Amount | £434,700 (GBP) |
| Funding ID | MR/T015055/1 |
| Organisation | Medical Research Council (MRC) |
| Sector | Public |
| Country | United Kingdom |
| Start | 03/2020 |
| End | 02/2023 |
| Description | Haematopoiesis - Novel tools for modelling normal and perturbed haematopoiesis |
| Amount | £1,532,023 (GBP) |
| Funding ID | MC_PC_21043 |
| Organisation | Medical Research Council (MRC) |
| Sector | Public |
| Country | United Kingdom |
| Start | 03/2022 |
| End | 03/2027 |
| Description | Hierarchical organization of haematopoietic stem- and progenitor cell populations during steady state and stress haematopoiesis |
| Amount | £3,329,263 (GBP) |
| Funding ID | MC_UU_00029/9 |
| Organisation | Medical Research Council (MRC) |
| Sector | Public |
| Country | United Kingdom |
| Start | 03/2022 |
| End | 03/2027 |
| Description | LMO4 as a drug target in mast cell malignancies |
| Amount | £201,659 (GBP) |
| Funding ID | 23024 |
| Organisation | Blood Cancer UK |
| Sector | Charity/Non Profit |
| Country | United Kingdom |
| Start | 03/2024 |
| End | 09/2025 |
| Description | Transcriptional and epigenetic mechanisms of HSC subtype diversification |
| Amount | £462,191 (GBP) |
| Funding ID | BB/V002198/1 |
| Organisation | Biotechnology and Biological Sciences Research Council (BBSRC) |
| Sector | Public |
| Country | United Kingdom |
| Start | 03/2021 |
| End | 11/2024 |
| Title | Deconvolution of HSC populations using ATACseq |
| Description | We developed a computational method to estimate the composition of HSC populations using epigenetic signatures of fate-restricted HSCs. |
| Type Of Material | Technology assay or reagent |
| Year Produced | 2023 |
| Provided To Others? | Yes |
| Impact | Will allow assessment of HSC diversity without the use of large numbers of mice for single HSC transplanatation. |
| Description | Hematopoiesis and leukemogenesis |
| Organisation | CeMM Research Center for Molecular Medicine |
| Country | Austria |
| Sector | Academic/University |
| PI Contribution | Genetic modelling of hematopoiesis |
| Collaborator Contribution | Scientific discussion, methodology |
| Impact | Mancini E, Sanjuan-Pla A, Luciani L, Moore S, Grover A, Zay A, Rasmussen KD, Luc S, Bilbao D, O'Carroll D, Jacobsen SE, Nerlov C. FOG-1 and GATA-1 act sequentially to specify definitive megakaryocytic and erythroid progenitors. EMBO J. 2011 Nov 8. doi: 10.1038/emboj.2011.390 Kharazi S, Mead AJ, Mansour A, Hultquist A, Böiers C, Luc S, Buza-Vidas N, Ma Z, Ferry H, Atkinson D, Reckzeh K, Masson K, Cammenga J, Rönnstrand L, Arai F, Suda T, Nerlov C, Sitnicka E, Jacobsen SE. Impact of gene dosage, loss of wild-type allele, and FLT3 ligand on Flt3-ITD-induced myeloproliferation. Blood. 2011 Sep 29;118(13):3613-21. Kaveri D., P. Kastner, D. Dembélé, C. Nerlov, S. Chan and P. Kirstetter. 2013. ß-catenin activation synergizes with Pten loss and Myc overexpression in Notch-independent T-ALL. Blood 122: 694-704. Zhang,H., M. Alberich-Jordà, G. Amabile, H. Yang, P.B. Staber, A. DiRuscio, R.S. Welner, A. Ebralidze, J. Zhang, E. Levantini, V. Lefebvre, P.J.M. Valk, R. Delwel, M. Hoogenkamp, C. Nerlov, J. Cammenga, B. Saez, D.T. Scadden, C. Bonifer, M. Ye and D.G. Tenen. 2013. Sox4 is a key oncogenic target in C/EBPa mutant Acute Myeloid Leukemia. Cancer Cell 24: 575-88. Grebien, F., M. Vedadi, M. Getlik, R. Giambruno, A. Grover, R. Avellino, A. Skucha, S. Vittori, E. Kuznetsova, D. Smil, D. Barsyte-Lovejoy, F. Li, G. Poda, M. Schapira, H. Wu, A. Dong, G. Senisterra, A. Stukalov, K.V.M. Huber, A. Schönegger, M. Bilban, C. Bock, P.J. Brown, J. Zuber, K.L. Bennett, R. Al-awar, R. Delwel, C. Nerlov, C.H. Arrowsmith and G. Superti-Furga. 2015. Pharmacological targeting of the Wdr5-MLL interaction in C/EBPa N-terminal leukemia. Nat. Chem. Biol. 11: 571-8. |
| Start Year | 2018 |
| Description | Hematopoiesis and leukemogenesis |
| Organisation | Harvard University |
| Department | Harvard Stem Cell Institute |
| Country | United States |
| Sector | Academic/University |
| PI Contribution | Genetic modelling of hematopoiesis |
| Collaborator Contribution | Scientific discussion, methodology |
| Impact | Mancini E, Sanjuan-Pla A, Luciani L, Moore S, Grover A, Zay A, Rasmussen KD, Luc S, Bilbao D, O'Carroll D, Jacobsen SE, Nerlov C. FOG-1 and GATA-1 act sequentially to specify definitive megakaryocytic and erythroid progenitors. EMBO J. 2011 Nov 8. doi: 10.1038/emboj.2011.390 Kharazi S, Mead AJ, Mansour A, Hultquist A, Böiers C, Luc S, Buza-Vidas N, Ma Z, Ferry H, Atkinson D, Reckzeh K, Masson K, Cammenga J, Rönnstrand L, Arai F, Suda T, Nerlov C, Sitnicka E, Jacobsen SE. Impact of gene dosage, loss of wild-type allele, and FLT3 ligand on Flt3-ITD-induced myeloproliferation. Blood. 2011 Sep 29;118(13):3613-21. Kaveri D., P. Kastner, D. Dembélé, C. Nerlov, S. Chan and P. Kirstetter. 2013. ß-catenin activation synergizes with Pten loss and Myc overexpression in Notch-independent T-ALL. Blood 122: 694-704. Zhang,H., M. Alberich-Jordà, G. Amabile, H. Yang, P.B. Staber, A. DiRuscio, R.S. Welner, A. Ebralidze, J. Zhang, E. Levantini, V. Lefebvre, P.J.M. Valk, R. Delwel, M. Hoogenkamp, C. Nerlov, J. Cammenga, B. Saez, D.T. Scadden, C. Bonifer, M. Ye and D.G. Tenen. 2013. Sox4 is a key oncogenic target in C/EBPa mutant Acute Myeloid Leukemia. Cancer Cell 24: 575-88. Grebien, F., M. Vedadi, M. Getlik, R. Giambruno, A. Grover, R. Avellino, A. Skucha, S. Vittori, E. Kuznetsova, D. Smil, D. Barsyte-Lovejoy, F. Li, G. Poda, M. Schapira, H. Wu, A. Dong, G. Senisterra, A. Stukalov, K.V.M. Huber, A. Schönegger, M. Bilban, C. Bock, P.J. Brown, J. Zuber, K.L. Bennett, R. Al-awar, R. Delwel, C. Nerlov, C.H. Arrowsmith and G. Superti-Furga. 2015. Pharmacological targeting of the Wdr5-MLL interaction in C/EBPa N-terminal leukemia. Nat. Chem. Biol. 11: 571-8. |
| Start Year | 2018 |
| Description | Hematopoiesis and leukemogenesis |
| Organisation | Medical Research Council (MRC) |
| Department | MRC Molecular Haematology Unit |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | Genetic modelling of hematopoiesis |
| Collaborator Contribution | Scientific discussion, methodology |
| Impact | Mancini E, Sanjuan-Pla A, Luciani L, Moore S, Grover A, Zay A, Rasmussen KD, Luc S, Bilbao D, O'Carroll D, Jacobsen SE, Nerlov C. FOG-1 and GATA-1 act sequentially to specify definitive megakaryocytic and erythroid progenitors. EMBO J. 2011 Nov 8. doi: 10.1038/emboj.2011.390 Kharazi S, Mead AJ, Mansour A, Hultquist A, Böiers C, Luc S, Buza-Vidas N, Ma Z, Ferry H, Atkinson D, Reckzeh K, Masson K, Cammenga J, Rönnstrand L, Arai F, Suda T, Nerlov C, Sitnicka E, Jacobsen SE. Impact of gene dosage, loss of wild-type allele, and FLT3 ligand on Flt3-ITD-induced myeloproliferation. Blood. 2011 Sep 29;118(13):3613-21. Kaveri D., P. Kastner, D. Dembélé, C. Nerlov, S. Chan and P. Kirstetter. 2013. ß-catenin activation synergizes with Pten loss and Myc overexpression in Notch-independent T-ALL. Blood 122: 694-704. Zhang,H., M. Alberich-Jordà, G. Amabile, H. Yang, P.B. Staber, A. DiRuscio, R.S. Welner, A. Ebralidze, J. Zhang, E. Levantini, V. Lefebvre, P.J.M. Valk, R. Delwel, M. Hoogenkamp, C. Nerlov, J. Cammenga, B. Saez, D.T. Scadden, C. Bonifer, M. Ye and D.G. Tenen. 2013. Sox4 is a key oncogenic target in C/EBPa mutant Acute Myeloid Leukemia. Cancer Cell 24: 575-88. Grebien, F., M. Vedadi, M. Getlik, R. Giambruno, A. Grover, R. Avellino, A. Skucha, S. Vittori, E. Kuznetsova, D. Smil, D. Barsyte-Lovejoy, F. Li, G. Poda, M. Schapira, H. Wu, A. Dong, G. Senisterra, A. Stukalov, K.V.M. Huber, A. Schönegger, M. Bilban, C. Bock, P.J. Brown, J. Zuber, K.L. Bennett, R. Al-awar, R. Delwel, C. Nerlov, C.H. Arrowsmith and G. Superti-Furga. 2015. Pharmacological targeting of the Wdr5-MLL interaction in C/EBPa N-terminal leukemia. Nat. Chem. Biol. 11: 571-8. |
| Start Year | 2018 |
| Description | Hematopoiesis and leukemogenesis |
| Organisation | University of Birmingham |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | Genetic modelling of hematopoiesis |
| Collaborator Contribution | Scientific discussion, methodology |
| Impact | Mancini E, Sanjuan-Pla A, Luciani L, Moore S, Grover A, Zay A, Rasmussen KD, Luc S, Bilbao D, O'Carroll D, Jacobsen SE, Nerlov C. FOG-1 and GATA-1 act sequentially to specify definitive megakaryocytic and erythroid progenitors. EMBO J. 2011 Nov 8. doi: 10.1038/emboj.2011.390 Kharazi S, Mead AJ, Mansour A, Hultquist A, Böiers C, Luc S, Buza-Vidas N, Ma Z, Ferry H, Atkinson D, Reckzeh K, Masson K, Cammenga J, Rönnstrand L, Arai F, Suda T, Nerlov C, Sitnicka E, Jacobsen SE. Impact of gene dosage, loss of wild-type allele, and FLT3 ligand on Flt3-ITD-induced myeloproliferation. Blood. 2011 Sep 29;118(13):3613-21. Kaveri D., P. Kastner, D. Dembélé, C. Nerlov, S. Chan and P. Kirstetter. 2013. ß-catenin activation synergizes with Pten loss and Myc overexpression in Notch-independent T-ALL. Blood 122: 694-704. Zhang,H., M. Alberich-Jordà, G. Amabile, H. Yang, P.B. Staber, A. DiRuscio, R.S. Welner, A. Ebralidze, J. Zhang, E. Levantini, V. Lefebvre, P.J.M. Valk, R. Delwel, M. Hoogenkamp, C. Nerlov, J. Cammenga, B. Saez, D.T. Scadden, C. Bonifer, M. Ye and D.G. Tenen. 2013. Sox4 is a key oncogenic target in C/EBPa mutant Acute Myeloid Leukemia. Cancer Cell 24: 575-88. Grebien, F., M. Vedadi, M. Getlik, R. Giambruno, A. Grover, R. Avellino, A. Skucha, S. Vittori, E. Kuznetsova, D. Smil, D. Barsyte-Lovejoy, F. Li, G. Poda, M. Schapira, H. Wu, A. Dong, G. Senisterra, A. Stukalov, K.V.M. Huber, A. Schönegger, M. Bilban, C. Bock, P.J. Brown, J. Zuber, K.L. Bennett, R. Al-awar, R. Delwel, C. Nerlov, C.H. Arrowsmith and G. Superti-Furga. 2015. Pharmacological targeting of the Wdr5-MLL interaction in C/EBPa N-terminal leukemia. Nat. Chem. Biol. 11: 571-8. |
| Start Year | 2018 |
| Description | Hematopoietic lineage commitment |
| Organisation | ETH Zurich |
| Country | Switzerland |
| Sector | Academic/University |
| PI Contribution | We use single cell transcriptome analysis and lineage tracing, combined with single cell lineage readouts, to map cellular heterogeneity, differentiation trajectories, and lineage potentials of hematopoietic stem- and progenitor cells |
| Collaborator Contribution | The partner uses fluorescent reporters and live imaging technology to identify transcriotionally distinct cell subsets and to follow cellular behaviour |
| Impact | PMID: 27411635 PMID: 30301719 |
| Start Year | 2014 |
| Description | Imaging of stem cell-niche interactions |
| Organisation | Karolinska Institute |
| Department | Department of Cell and Molecular Biology |
| Country | Sweden |
| Sector | Academic/University |
| PI Contribution | Development of mouse models to identify cell-cell contact between stem cells and their niches in vivo using fluorescent complementation |
| Collaborator Contribution | Use of mouse models in neuronal and other non-hematopoietic tissues |
| Impact | No publications yet |
| Start Year | 2012 |