Cellular mechanisms of haematopoietic lineage commitment

Lead Research Organisation: University of Oxford

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.
 
Description Danish Cancer Research Society
Geographic Reach Europe 
Policy Influence Type Membership of a guideline committee
Impact Funding allocation, clinical and basic cancer research
 
Description Danish Medical Research Council
Geographic Reach National 
Policy Influence Type Participation in advisory committee
Impact Increased funding for academic training of medical doctors, improved recruitment of early stage medicine student to research.
 
Description BBSRC Project Grant
Amount £341,857 (GBP)
Organisation Biotechnology and Biological Sciences Research Council (BBSRC) 
Sector Public
Country United Kingdom
Start 11/2015 
End 05/2018
 
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 12/2020 
End 11/2023
 
Title Intraperitoneal transplantation as a means to detect all myeloid developmental potentials 
Description We have developed direct transplantation of myeloid progenitors into the peritoneum of Kit-deficient W41 mice as an assays capable of detecting the formation of all myeloid innate immune cell types from a specific cell population. 
Type Of Material Technology assay or reagent 
Provided To Others? No  
Impact Manuscript in press, too early to determine impact. 
 
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 Blog on platelet-biased hematopoietic stem cells. 
Form Of Engagement Activity Engagement focused website, blog or social media channel
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Blog describing the identification of a new stem cell dedicated to preferential and rapid production of platelets (primary research published in Nature)
Year(s) Of Engagement Activity 2013
URL http://www.imm.ox.ac.uk/propagating-platelets-a-novel-cancer-therapy
 
Description Living library 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact Public event where members of the public meet individually with researchers to discuss preset topics (the titles of the books - one or more can be chosen on site).
Year(s) Of Engagement Activity 2019
URL https://visit.bodleian.ox.ac.uk/event/if-at-the-bodleian