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.
People |
ORCID iD |
Claus Nerlov (Principal Investigator) |
Publications
Brown E
(2018)
Multiple membrane extrusion sites drive megakaryocyte migration into bone marrow blood vessels.
in Life science alliance
Braun TP
(2019)
Myeloid lineage enhancers drive oncogene synergy in CEBPA/CSF3R mutant acute myeloid leukemia.
in Nature communications
Mead AJ
(2017)
Niche-mediated depletion of the normal hematopoietic stem cell reservoir by Flt3-ITD-induced myeloproliferation.
in The Journal of experimental medicine
Lopez CK
(2019)
Ontogenic Changes in Hematopoietic Hierarchy Determine Pediatric Specificity and Disease Phenotype in Fusion Oncogene-Driven Myeloid Leukemia.
in Cancer discovery
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
Related Projects
Project Reference | Relationship | Related To | Start | End | Award Value |
---|---|---|---|---|---|
MC_UU_00016/1 | 01/04/2017 | 31/03/2022 | £3,035,000 | ||
MC_UU_00016/2 | Transfer | MC_UU_00016/1 | 01/04/2017 | 31/03/2022 | £3,411,000 |
MC_UU_00016/3 | Transfer | MC_UU_00016/2 | 01/04/2017 | 31/03/2022 | £1,366,000 |
MC_UU_00016/4 | Transfer | MC_UU_00016/3 | 01/04/2017 | 31/03/2020 | £3,017,000 |
MC_UU_00016/5 | Transfer | MC_UU_00016/4 | 01/04/2017 | 31/03/2020 | £497,000 |
MC_UU_00016/6 | Transfer | MC_UU_00016/5 | 01/04/2017 | 31/03/2022 | £2,530,000 |
MC_UU_00016/7 | Transfer | MC_UU_00016/6 | 01/04/2017 | 31/03/2022 | £2,018,000 |
MC_UU_00016/8 | Transfer | MC_UU_00016/7 | 01/04/2017 | 31/03/2018 | £1,131,000 |
MC_UU_00016/9 | Transfer | MC_UU_00016/8 | 01/04/2017 | 31/03/2022 | £2,500,000 |
MC_UU_00016/10 | Transfer | MC_UU_00016/9 | 01/04/2017 | 31/03/2018 | £1,171,000 |
MC_UU_00016/11 | Transfer | MC_UU_00016/10 | 01/04/2017 | 31/03/2022 | £1,387,000 |
MC_UU_00016/12 | Transfer | MC_UU_00016/11 | 01/04/2017 | 31/03/2022 | £446,000 |
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 | 04/2022 |
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 | 04/2022 |
End | 03/2027 |
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 | 04/2021 |
End | 11/2024 |
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 |