Transcriptional regulation of hematopoietic self-renewal, lineage specification and leukemogenesis

Lead Research Organisation: University of Oxford
Department Name: Weatherall Inst of Molecular Medicine

Abstract

The blood system is necessary for many functions of the body, and also gives rise to several types of cancer. In this project we will try to understand how the many blood cell types are specified from a sibgle stem cell, and how this process is disturbed in leukemias. By using the body?s own molecules to alter the fate of the stem cells we will analyze if leukemia development can be accelerated and delayed by signals normally used to increase the production of white and red blood cells, respectively

Technical Summary

The purpose of the proposed Programme is to conduct an integrated research projects addressing how intrinsic regulators (transcription factors) and extrinsic cues (cytokines) interact to control the lineage commitment and self-renewal of hematopoietic cells, specifically through modulation of of their lineage priming and gene expression. We will also investigate the role played by these processes in the formation of leukemic stem cells in CEBPA mutant AML. To achieve this we will use conditional genetics to specifically eliminate intrinsic regulators (GATA-1, FOG-1, C/EBPa) and activate cytokine/growth factor receptors (Flt3, GM-CSFR, EpoR), and generate genetically precise models of human AML. The analysis of the hematopoietic system by flow cytometry will be complemented by characterization of the transcriptional changes induced, as well as studeis of the kinetics by which leukemic stem cells arise, and how this is modulated by extrinsic signals.

Publications

10 25 50
 
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 AICR Project Grant
Amount £212,400 (GBP)
Funding ID 11-0724 
Organisation Association for International Cancer Research 
Sector Charity/Non Profit
Country United Kingdom
Start 10/2011 
End 09/2015
 
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 Gordon Piller Studentship
Amount £138,724 (GBP)
Funding ID 13064 
Organisation The Leukemia & Lymphoma Society 
Sector Charity/Non Profit
Country United States
Start 10/2014 
End 09/2018
 
Description LLR Project Grant
Amount £233,598 (GBP)
Funding ID 13008 
Organisation Leukaemia and Lymphoma Research 
Sector Charity/Non Profit
Country United Kingdom
Start 11/2013 
End 10/2016
 
Description LLR Project Grant
Amount £175,487 (GBP)
Organisation Leukaemia and Lymphoma Research 
Sector Charity/Non Profit
Country United Kingdom
Start 01/2016 
End 12/2017
 
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 Complete hematopoietic reporter mouse 
Description Using BAC transgenes expressing EGFP at high levels in platelets and erythoid cells we have generated a mouse line where production of cells of all lineages (myeloid, lymphoid, platelet, erythroid) from a stem cell or progenitor population can be monitored 
Type Of Material Technology assay or reagent 
Year Produced 2011 
Provided To Others? Yes  
Impact One publication: 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 
 
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 In vivo imaging of platelet formation 
Organisation University College London
Department School of Life and Medical Sciences
Country United Kingdom 
Sector Academic/University 
PI Contribution We provides fluorescent reporter mice to selectively label megakaryocyte-lineage cells in vivo
Collaborator Contribution In vivo imaging and cryo-EM analysis
Impact Manuscript submitted.
Start Year 2014
 
Description In vivo imaging of platelet formation 
Organisation University of Bristol
Department School of Physiology, Pharmacology and Neuroscience
Country United Kingdom 
Sector Academic/University 
PI Contribution We provides fluorescent reporter mice to selectively label megakaryocyte-lineage cells in vivo
Collaborator Contribution In vivo imaging and cryo-EM analysis
Impact Manuscript submitted.
Start Year 2014
 
Description Oncogene collaboration in myeloid leukemogenesis 
Organisation Lund University
Department Lund Stem Cell Centre
Country Sweden 
Sector Academic/University 
PI Contribution Generation of an accurate model for CEBPA mutant AML
Collaborator Contribution Providing an knockin model for FLT3-ITD mutations
Impact Publication: Reckzeh, K., O. Bereshchenko, A. Mead, M. Rehn, S. Kharazi, S.E. Jacobsen, C. Nerlov* and J. Cammenga*. 2012. Molecular and Cellular Effects of Oncogene Cooperation in a Genetically Accurate AML Mouse Model. Leukemia 26: 1527-36. (* Equal contribution).
Start Year 2008
 
Description Blog on emergency erythropoiesis 
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 a new model for how the body responds to anaemia, based on a publication in Journal of Experimental Medicine, published on the institute web site.
Year(s) Of Engagement Activity 2014
URL http://www.imm.ox.ac.uk/how-to-make-a-red-blood-cell-and-fast
 
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