Professor Constanze Bonifer

Professor Constanze Bonifer

Department of Cancer and Genomic Sciences
Emeritus Professor of Experimental Haematology

Contact details

Email
c.bonifer@bham.ac.uk
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Address
Department of Cancer and Genomic Sciences
University of Birmingham
Edgbaston
Birmingham
B15 2TT
UK

My name is Constanze Bonifer, I am Emeritus Professor of Experimental Haematology in the Department of Cancer and Genomic Sciences  and I am an Honorary Professor at the University of Melbourne, Australia.

Our lab worked on gene regulation in the hematopoietic system. We studied how transcription factors and chromatin components drive differential gene expression during blood cell development, both in a normal, but also in a disease setting. We were particularly interested into studying at the genome-wide level, how mutant transcription factors that cause acute myeloid leukaemia reprogram the chromatin landscape and gene expression of normal cells and maintain aberrant malignant phenotypes. To answer these questions, we used a number of different techniques, from classical molecular biology, to sophisticated cell culture such as embryonic stem cell differentiation to working with primary cells from leukaemia patients. My lab in Birmingham closed at the end of 2023.

Qualifications

  • 1995 Habilitation in Molecular Biology and Genetics, University of Freiburg, Germany
  • 1985 PhD in Natural Sciences 1985, University of Heidelberg, Germany

 

Biography

Constanze Bonifer studied Biology at the University of Cologne, Germany and graduated 1980 with a first class degree in Biochemistry, Chemistry and Genetics. She then went on to do a PhD in Biochemistry and Molecular Biology, first at the University of Cologne, then at the Centre for Molecular Biology, University of Heidelberg.

This was followed by Postdoctoral training periods at the Karolinska Institute, Stockholm, and the National Institute for Medical Research in London where she started to work on gene regulation.

1990 she became Assistant Professor and independent group leader at University of Freiburg, Germany, where she worked on gene regulation in the hematopoietic system.

1997 she went back to the UK and became a group leader at the Molecular Medicine Unit, University of Leeds, where she started to work not only on basic mechanisms controlling blood cell development, but also on epigenetic mechanisms controlling leukemogenesis.

She became a Reader in 2000, a Professor in 2003 and in 2004 became a full Professor and Chair of Experimental Haematology. In 2006 she was appointed Head of Section of Experimental Haematology at the Leeds Institute of Molecular Medicine.

From August 2011 to December 2023, Constanze was Chair of Experimental Haematology in Birmingham.

Between 2015 and 2020 she led  the Section of Genome Structure and Function in the Institute of Cancer and Genomic Sciences.

Whilst at Birmingham Constanze held a programme grant from Bloodwise, as well as grants from the BBSRC, the MRC, CRUK and the Kay Kendall Leukaemia fund, together with several studentships.

Research

The main research interest of the Bonifer lab was to study the mechanism of cell fate decisions in the haematopoietic system at the level of gene regulation. A number of diseases such as leukaemia affect blood cell development, an understanding of the molecular basis of hematopoietic cell differentiation is therefore of utmost importance for the development of new therapeutic strategies. We wanted to understand how different genetic programs are activated and silenced at specific stages of hematopoiesis and which factors are involved in this process.

Research Undertaken

A large body of evidence from genetic studies demonstrates that transcription factors interacting with the chromatin modification machinery play essential roles in all phases of the development of multicellular organisms. At individual genes, these epigenetic regulatory proteins influence the transcriptional status, the chromatin structure and the spectrum of biochemical tags attached to individual chromatin components. Such epigenetic events underlay all cell fate decisions and are the basis for the progressive restriction in the developmental potential of all stem cell types. They are also responsible for aberrant cell differentiation in leukaemia. However, very little is known about the molecular details of these processes.

To address the issue of cell specification and cell lineage restriction at the molecular level we studied the regulation of chromatin structure of genes expressed in the myeloid lineage of the hematopoietic system. We identified the order of events taking place during the developmentally controlled activation of genes and we studied how genes are epigenetically silenced. Our research has shown that even before the onset of gene expression and stable transcription factor binding, chromatin of lineage specific genes is partially accessible and transiently bound by transcription factors, and that the silencing of genes during the differentiation of alternative lineages occurs in defined and distinct steps. We also gained insights in the epigenetic consequences of the action of nuclear oncoproteins involved in leukaemia. 

To examine the full complexity of regulatory interactions at the genome, we performed research along the following lines:

1)    We studied the role of chromatin structure components and specific transcription factors in the activation of genes specific for a given differentiation pathway.

2)    We used the differentiation of mouse and human embryonic stem cells into hematopoietic cells as models to gain insights into how transcription factors program chromatin. Our work has identified a core transcriptional network driving hematopoietic specification (Goode et al., 2016) and made a first in-road into how signalling responsive transcription factors shape the epigenome (Obier et al., Development 2016; Gilmour et al., 2014, 2018). We also used these systems to gain insights into the first genomic events after the expression of specific oncogenes (Regha et al., 2015, Kellaway et al., 2020, Nafria et al., 2020)

3)    We analyzed the impact of mutations in transcription factor and chromatin modifier genes on blood cell development in a system-wide fashion using Next Generation Sequencing approaches such as DNase-Seq, ATAC-Seq, ChIP-Seq and  RNA-Seq (bulk and single cell).

4)    It is now absolutely clear that cancer is disease of aberrant gene regulation. A large part of our research was devoted to the question of how the epigenome is reprogrammed in leukaemia (Ptasinska et al., 2014; Cauchy et al., 2015; Assi et al., 2019). Jointly with the lab of Professor Peter Cockerill, we investigated aberrant human blood cell differentiation processes in a system-wide fashion using multi-omics approaches. The aim of these studies was to identify gene tumour specific gene regulatory networks and find those components that are required for tumour development and maintenance.  (https://www.birmingham.ac.uk/university/colleges/mds/news/2018/11/bonifer-leukaemia.aspx)

One of the great challenges for future biological research will be to understand in a system-wide fashion how cell fate decisions are regulated and how such decisions are derailed in malignant cells. We do not know how the ordered interplay of transcription factors and specific chromatin states eventually leads to the stable expression of lineage specific genetic programs. We collaboratied with computational biologists to reconstruct dynamic and global models of the molecular interactions governing blood cell development.

Such information is vital for our translational research program. Interactions between transcription factors and epigenetic regulatory proteins are at the heart of normal and malignant cell differentiation processes and we consider our basic research as a necessary prerequisite to our ongoing efforts to understand and target primary and secondary events in tumour formation in the nucleus of a cell.

Other activities

Constanze Bonifer was a member of the Executive Group and was the Founding Director of the Birmingham Centre for Genome Biology. She was a member of the International Society of Experimental Haematology (ISEH) and a member of the Editorial Board of Experimental Hematology.

Conny was also the joint Theme Lead of Cancer Genomics research theme for the Cancer Research UK Birmingham Centre and was Theme Lead for Genomics.

She was the co-organizer of Cancer Epigenetics conference, May 2013 and the Birmingham Centre for Genome Biology meetings on Genome Biology, 2016- 2019.

Professor Bonifer is a frequent reviewer for international journals (Cell, EMBO J, Genes & Development, J. Experimental Medicine, Nature Genetics, Blood, Stem Cells, Leukemia, Mol. Cell. Biology, J. Biol. Chemistry, PNAS, Human Molecular Genetics, Nucleic Acids Research, Gene, Genome Biology), and also reviews national and international grant proposals and as member of site visit panels. 

Between 2003 and 2008 she served on Committee C of the BBSRC, 2009 and 2012 she was a member of the Bloodwise Career and Fellowship panel, between 2012 and 2014 she was Vice-Chair of Committee C of the BBSRC, between 2017 and 2020 she served for the non-clinical career development fellowship panel for the MRC and is now working for the BBSRC. Over the last 15 years she also was a regular member of site-visit panels for the Deutsche Forschungsgemeinschaft (DFG).

Publications

Constanze Bonifer currently lists 142 publications in PubMed. Here are selected peer reviewed publications from the last ten years:

 Lamprecht, B., Walter, K., Kreher, S., Kumar, R., Hummel, M., Lenze, D., Köchert, K., Bouhlel, M.A., Richter, J., Soler, E., Stadhouders, R., Jöhrens, C., Wurster, K.D., Callen, C., Harte, M.F., Giefing, M., Barlow, R., Stein, H., Anagnostopoulos, I., Janz, M., Cockerill, P.N., Siebert, R., Dörken, B., Bonifer, C.*, and Mathas, S.* (2010). (*Joint corresponding authors). De–repression of an endogenous long terminal repeat activates the CSF1R proto–oncogene in human lymphoma. Nature Medicine. 16, 571 - 579

Leddin, M., Perrod, C. , Hoogenkamp, M., Ghani, S., Ass, S., Heinz,S., Wilson, N.K., Follows, G., Schönheit,J., Vockentanz,L., Mosamam,A., Chen, W., Tenen, D.G., Westhead, D.R., Göttgens, B., Bonifer, C*. and Rosenbauer, F*. (2011) (*joint corr. authors). Two distinct auto-regulatory loops operate at the Pu.1 locus in B cells and myeloid cells. Blood. Mar 10;117(10):2827-38

Levantini E, Lee S, Radomska HS, Hetherington CJ, Alberich-Jorda M, Amabile G, Zhang P, Gonzalez DA, Zhang J, Basseres DS, Wilson NK, Koschmieder S, Huang G, Zhang DE, Ebralidze AK, Bonifer C, Okuno Y, Göttgens B, Tenen DG. (2011). RUNX1 regulates the CD34 gene in haematopoietic stem cells by mediating interactions with a distal regulatory element. EMBO J. 30 :4059-4070

Ptasinska, A.; Assi, S.A., James, S.R.,Williamson, D.,Hoogenkamp, M., Mengchu, W., Care, M., McNeill, H., Cullen, M., Tooze, R., Tenen, D.G., Cockerill, P.N. Westhead, D.R.,Heidenreich, O. and Bonifer, C. (2012). Reversible genome-wide epigenetic reprogramming by the leukemia-initiating fusion protein RUNX1/ETO. Leukemia 26:1829-41

Lancrin, C., Mazan, M., Stefanska, M., Lichtinger, M., Costa, G., Vargel, O., Wilson, N., Möröy, T., Bonifer, C., Göttgens, B., Kouskoff, V., and Lacaud, G. (2012) Critical function of GFI1 and GFI1B at the onset of hematopoietic development. Blood 120, 314 – 322

Lichtinger, M., Ingram, R.M., Hannah, R., Clarke, D., Müller, D., Lie-A-Ling, M., Noailles, L., Zhang, P., Wu, M., Tenen, D.G., Assi, S., Westhead, D.R., Kouskoff, V., Lacaud, G., Göttgens, B., and Bonifer, C. (2012) RUNX1 reshapes the epigenetic landscape at the onset of hematopoietic development. EMBO J.  31:4318-33

The histone methyltransferase KMT2B is required for RNA polymerase II association and protection from DNA methylation at the MagohB CpG island promoter. Ladopoulos, V., Hofemeister, H., Hoogenkamp, M., Riggs, A.D. Stewart, A.F. and Bonifer, C (2013). Mol Cell Biol. 33(7):1383-1393

Ray, D., Kwon, S.Y., Tagoh, H., Heidenreich, O., Ptasinska, A. and Bonifer, C (2013). Lineage inappropriate PAX5 expression in t(8;21) acute myeloid leukemia requires signalling mediated abrogation of polycomb repression. Blood. 122(5):759-69

Zhang H, Alberich-Jorda M, Amabile G, Yang H, Staber PB, Di Ruscio A, Welner RS, Ebralidze A, Zhang J, Levantini E, Lefebvre V, Valk PJ, Delwel R, Hoogenkamp M, Nerlov C, Cammenga J, Saez B, Scadden DT, Bonifer C, Ye M, Tenen DG. (2013). Sox4 is a key oncogenic target in C/EBPα mutant acute myeloid leukemia. Cancer Cell. 24(5):575-88.

Piper, J., Elze. MC., Cauchy, P., Cockerill, P.N*., Bonifer,C*., Ott, S*. (*joint corr authors) Wellington: A novel method for the accurate identification of digital genomic footprints from DNase-seq data. Nucleic Acids Res. 2013 Nov;41(21):e201.

Gilmour, J., Assi, S.A., Jaegle, U., Kulu, D., van der Werken, H., Clarke, D., Westhead, D.R., Philipsen, S. and Bonifer,C. (2014) A crucial role of the ubiquitously expressed transcription factor Sp1 at early stages of hematopoietic specification. Development. Jun;141(12):2391-401

Lie-A-Ling M, Marinopoulou E, Li Y, Patel R, Stefanska M, Bonifer C, Miller C, Kouskoff V, Lacaud G. RUNX1 positively regulates a cell adhesion and migration program in murine hemogenic endothelium prior to blood emergence. Blood. 2014 Sep 11;124(11):e11-20.

Ptasinska A, Assi SA, Martinez-Soria N, Imperato MR, Piper J, Cauchy P, Pickin A, James SR, Hoogenkamp M, Williamson D, Wu M, Tenen DG, Ott S, Westhead DR, Cockerill PN, Heidenreich O, Bonifer C. Identification of a dynamic core transcriptional network in t(8;21) AML that regulates differentiation block and self-renewal. Cell Reports. 2014 Sep 25;8(6):1974-88.

Kreher S, Bouhlel MA, Cauchy P, Lamprecht B, Li S, Grau M, Hummel F, Köchert K, Anagnostopoulos I, Jöhrens K, Hummel M, Hiscott J, Wenzel SS, Lenz P, Schneider M, Küppers R, Scheidereit C, Giefing M, Siebert R, Rajewsky K, Lenz G, Cockerill PN, Janz M, Dörken B, Bonifer C*, Mathas S* (joint corr. authors). Mapping of transcription factor motifs in active chromatin identifies IRF5 as key regulator in classical Hodgkin lymphoma. Proc Natl Acad Sci U S A. 2014 Oct 21;111(42):E4513-22.

Regha K, Assi SA, Tsoulaki O, Gilmour J, Lacaud G, Bonifer C. (2014) Developmental-stage-dependent transcriptional response to leukaemic oncogene expression. Nature Commun. 2015 May 28;6:7203.

Cauchy P, James SR, Zacarias-Cabeza J, Ptasinska A, Imperato MR, Assi SA, Piper J, Canestraro M, Hoogenkamp M, Raghavan M, Loke J, Akiki S, Clokie SJ, Richards SJ, Westhead DR, Griffiths MJ, Ott S, Bonifer C*, Cockerill PN* (joint corr. Authors). Chronic FLT3-ITD Signaling in Acute Myeloid Leukemia Is Connected to a Specific Chromatin Signature. Cell Rep. 2015 Aug 4;12(5):821-36.

van Oevelen C, Collombet S, Vicent G, Hoogenkamp M, Lepoivre C, Badeaux A, Bussmann L, Sardina JL, Thieffry D, Beato M, Shi Y, Bonifer C, Graf T. C/EBPα Activates Pre-existing and De Novo Macrophage Enhancers during Induced Pre-B Cell Transdifferentiation and Myelopoiesis. Stem Cell Reports. 2015 Aug 11;5(2):232-47.

Susumu Goyama*, Janet Schibler, Anjelika Gasilina, Shan Lin1 Kevin A. Link, Mahesh Shrestha, Jianjun Chen, Susan P. Whitman Clara D. Bloomfield, Salam Assi, Anetta Ptasinska, Olaf Heidenreich, Constanze Bonifer, Nicolas Nassar, James C. Mulloy (2015). UBASH3B (Sts-1)-CBL axis regulates myeloid proliferation in human AML1-ETO-induced leukemia. Leukemia 30, 728 – 739

Jason Piper, Salam A. Assi, Pierre Cauchy, Christophe Ladroue, Peter N. Cockerill*, Constanze Bonifer*, Sascha Ott,* (*Joint corr. Authors). (2015). Wellington-bootstrap: Differential DNase-seq footprinting identifies cell-type determining transcription factors. BMC Genomics. 16; 1000

Bevington SL, Cauchy P, Piper J, Bertrand E, Lalli N, Jarvis RC, Gilding LN, Ott S, Bonifer C, Cockerill PN. (2016). Inducible chromatin priming is associated with the establishment of immunological memory in T cells. EMBO J.;35(5):515-35.

Goode DK, Obier N, Vijayabaskar MS, Lie-A-Ling M, Lilly AJ, Hannah R, Lichtinger M, Batta K, Florkowska M, Patel R, Challinor M, Wallace K, Gilmour J, Assi SA, Cauchy P, Hoogenkamp M, Westhead DR, Lacaud G, Kouskoff V, Göttgens B, Bonifer C. (2016). Dynamic Gene Regulatory Networks Drive Hematopoietic Specification and Differentiation.  Dev Cell. 36(5):572-87

Illendula, A., Gilmour,J., Grembecka,J., Sesha Srimath Tirumala,V., Boulton, A., Kuntimaddi, A., Schmidt, C., Wang, L., Pullikan, J.A., Zong, H., Parlak, M., Kuscu, C., Pickin, A., Zhou, Y., Gao, Y., Mishra, L., Adli, M., Castilla, L.H., Rajewski, R.A., Janes, K.A., Guzman, M.L., Bonifer, C. and Bushweller, J.H. (2016). Small Molecule Inhibitor of CBFβ-RUNX Binding for RUNX Transcription Factor Driven Cancers. eBiomedicine. 2016 Jun;8:117-31

Lin S, Luo RT, Ptasinska A, Kerry J, Assi SA, Wunderlich M, Imamura T, Kaberlein JJ, Rayes A, Althoff MJ, Anastasi J, O'Brien MM, Meetei AR, Milne TA, Bonifer C, Mulloy JC, Thirman MJ. Instructive Role of MLL-Fusion Proteins Revealed by a Model of t(4;11) Pro-B Acute Lymphoblastic Leukemia.Cancer Cell. 2016 Nov 14;30(5):737-749.

Obier N, Cauchy P, Assi SA, Gilmour J, Lie-A-Ling M, Lichtinger M, Hoogenkamp M, Noailles L, Cockerill PN, Lacaud G, Kouskoff V, Bonifer C. Cooperative binding of AP-1 and TEAD4 modulates the balance between vascular smooth muscle and hemogenic cell fate. Development. 2016 Dec 1;143(23):4324-4340.

Loke J, Assi SA, Imperato MR, Ptasinska A, Cauchy P, Grabovska Y, Soria NM, Raghavan M, Delwel HR, Cockerill PN, Heidenreich O, Bonifer C. RUNX1-ETO and RUNX1-EVI1 Differentially Reprogram the Chromatin Landscape in t(8;21) and t(3;21) AML. Cell Rep. 2017 May 23;19(8):1654-1668. 

Lin S, Ptasinska A, Chen X, Shrestha M, Assi SA, Chin PS, Imperato MR, Aronow BJ, Zhang J, Weirauch MT, Bonifer C, Mulloy JC. A FOXO1-induced oncogenic network defines the AML1-ETO preleukemic program. Blood. 2017 Sep 7;130(10):1213-1222.

Martinez-Soria N, McKenzie L, Draper J, Ptasinska A, Issa H, Potluri S, Blair HJ, Pickin A, Isa A, Chin PS, Tirtakusuma R, Coleman D, Nakjang S, Assi S, Forster V, Reza M, Law E, Berry P, Mueller D, Elder A, Bomken SN, Pal D, Allan JM, Veal GJ, Cockerill PN, Wichmann C, Vormoor J, Lacaud G, Bonifer C*, Heidenreich O*. (*Joint corr. Authors). An Aberrant Transcription Factor Corrupts the Cell Cycle to Drive Leukemic Transformation. Cancer Cell 34(4):626-642.e8.

de Boer B, Prick J, Pruis MG, Keane P, Imperato MR, Jaques J, Brouwers-Vos AZ, Hogeling SM, Woolthuis CM, Nijk MT, Diepstra A, Wandinger S, Versele M, Attar RM, Cockerill PN, Huls G, Vellenga E, Mulder AB, Bonifer C*, Schuringa JJ (*Senior author). Prospective Isolation and Characterization of Genetically and Functionally Distinct AML Subclones. Cancer Cell 34(4):674-689.

Gilmour, J., Assi, S.A., Obier, N., and Bonifer, C. The Co-operation of RUNX1 with LDB1, CDK9 and BRD4 Drives Transcription Factor Complex Relocation During Haematopoietic Specification. Revision submitted to Scientific Reports 8(1):10410.

Assi SA, Imperato MR, Coleman DJL, Pickin A, Potluri S, Ptasinska A, Chin PS, Blair H, Cauchy P, James SR, Zacarias-Cabeza J, Gilding LN, Beggs A, Clokie S, Loke JC, Jenkin P, Uddin A, Delwel R, Richards SJ, Raghavan M, Griffiths MJ, Heidenreich O, Cockerill PN, Bonifer C. (2019) Subtype-specific regulatory network rewiring in acute myeloid leukemia. Nature Genetics. 51(1):151-162

Edginton-White B, Cauchy P, Assi SA, Hartmann S, Riggs AG, Mathas S, Cockerill PN, Bonifer C (2019). Global long terminal repeat activation participates in establishing the unique gene expression programme of classical Hodgkin lymphoma. Leukemia 33, 1463 - 1474. doi: 10.1038/s41375-018-0311-x.

Gilmour J, O'Connor L, Middleton CP, Keane P, Gillemans N, Cazier JB, Philipsen S, Bonifer C. (2019) Robust hematopoietic specification requires the ubiquitous Sp1 and Sp3 transcription factors. Epigenetics Chromatin. 2019 Jun 4;12(1):33.

Ptasinska A, Pickin A, Assi SA, Chin PS, Ames L, Avellino R, Gröschel S, Delwel R, Cockerill PN, Osborne CS, Bonifer C. (2020). RUNX1-ETO Depletion in t(8;21) AML Leads to C/EBPα- and AP-1-Mediated Alterations in Enhancer-Promoter Interaction. Cell Rep. 2019 Nov 12;29(7):2120.

Kellaway SG, Keane P, Kennett E, Bonifer C. (2020). RUNX1-EVI1 disrupts lineage determination and the cell cycle by interfering with RUNX1 and EVI1 driven gene regulatory networks. Haematologica. 2020 Apr 16:haematol.2019.241885. doi: 10.3324/haematol.2019.241885.

Nafria M, Keane P, Ng ES, Stanley EG, Elefanty AG, Bonifer C. (2020). Expression of RUNX1-ETO Rapidly Alters the Chromatin Landscape and Growth of Early Human Myeloid Precursor Cells. Cell Rep. 2020 May 26;31(8):107691.

 Book

Bonifer C, Cockerill PN (eds) Transcriptional and Epigenetic Mechanisms Regulating Normal and Aberrant Blood Cell Development. Epigenetics and Human Health, Springer, Heidelberg, 2014. ISBN 978-3-642-45198-0

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