WIMM PI
Curriculum Vitae
Personal Data
Name Claus Nerlov
Nationality Danish
Current position
Professor of Stem Cell Biology at the University of Oxford, United Kingdom
Previous positions
October 2008-September 2012: Professor of Stem Cell Biology, Head of Institute for Stem Cell Research and Associate Director, MRC Centre for Regenerative Medicine, University of Edinburgh, United Kingdom
October 2005-December 2012: Visiting Professor, Lund University, Lund, Sweden.
October 2001-December 2009: Group Leader in Mouse Biology, European Molecular Biology Laboratory, Monterotondo, Italy.
May 1998-October 2001: Head of the Laboratory of Gene Therapy Research, Copenhagen University Hospital, Denmark.
April 1995-April 1998: Postdoctoral Fellow with Professor Thomas Graf, Differentiation Program, European Molecular Biology Laboratory, Heidelberg, Germany
Research Achievements
Describe main research achievements to date (1977-2014) (max 300 words)
Ø My work on the transcriptional regulation of hematopoietic cell fate established mutual antagonism between lineage-instructive transcription factors (PU.1 vs. GATA-1; C/EBP vs. FOG-1; Genes Dev. 1998a, 1998b, 2000, Blood 2000) as a general mechanism for hematopoietic lineage segregation, establishing a key paradigm the general validity of which has been repeatedly demonstrated.
Ø We identified FOG-1 as a critical regulator of commitment to a megakaryocyte and erythroid fates: in its absence differentiation of these lineages is blocked at the bipotent preMegE stage (EMBO J., 2012). We showed that FOG-1 and C/EBPs prime HSCs in opposite directions: loss of C/EBP function leads to increased erythroid priming and decreased myeloid priming in HSCs, and loss of myeloid lineage commitment, whereas FOG-1 deletion has the opposite effect (Cancer Cell 2009; EMBO J. 2012). By eliminating Dicer in the hematopoietic system we observed a selective block in commitment to the erythroid lineage, concomitant with loss of erythroid programming in HSCs (Blood 2012). Overall, these findings established that the mechanisms that control lineage commitment also control HSC lineage priming.
Ø To directly address the role of lineage priming in specifying HSC fate we generated a reporter for the platelet-specific Vwf gene, and showed that Vwf expression defined a specific subset of long-term hematopoietic stem cells with significantly higher platelet output than their non-platelet primed counterparts (Nature 2013). Importantly, these platelet-biased HSCs were able to generate myeloid- and lymphoid-biased HSCs in serial transplantation experiments, demonstrating for the first time a hierarchical organization of self-renewing HSCs.
Ø Using C/EBPa as the model molecule, my laboratory provided the first genetic demonstration of a direct molecular coupling between cell cycle arrest and terminal differentiation (initially in adipocytes and neutrophils (Genes Dev. 2001; Cell 2001; JEM 2005), and subsequently in epidermal keratinocytes (Nat Cell Biol 2009). When CEBPA mutations were identified in AML patients we were the first to generate a genetically accurate mouse model, and demonstrate that these mutations were leukemogenic (Cancer Cell 2008, 2009) and collaborate with kinase-type oncogenes (Leukemia 2012).
What are the Future Aims of Your Current Group?
Please outline the main questions your group is addressing over the next 5 years (max 300 words)
Ø We will use our genetically accurate murine AML models (Cancer Cell 2008; 2009; Leukemia 2012) to identify specific intrinsic regulators of leukemia initiating cell function, and develop these as therapeutic targets. In addition, we will use the same models to address how leukemic cells impair normal hematopoiesis, and in particular hematopoietic stem cell function.
Ø We will further characterize biased murine HSC populations, using single cell gene profiling and single cell transplantation, as well the specific progenitor hierarchies they produce. We will extend these studies to human stem/progenitor cells, and study the population-based and intrinsic changes that occur during HSC aging in both species.
Ø We will study the molecular and cellular properties of hematopoietic stem cell and progenitor niches, identifying the cytokines and the cell types that produce these. Particular emphasis will be on niches specific for HSC subtypes and thymic progenitors, and the membrane-associated cytokines that provide localized signaling.
How do These Aims Contribute to the Understanding and/or Management of Human Disease
How do the aims of your research fit with the aims of the WIMM and Division of Medicine (max 300 words)
Ø The identification of molecular targets in leukemic stem cells will allow us to develop therapeutic strategies for AML. Characterization of the anti-hematopoietic effect of leukemic cells will help improve patient health and therapy resistance.
Ø The identification of novel HSC subtypes will allow prospective analysis of human stem cell grafts and potentially allow their stratification, as well provide more highly purified and functionally characterized stem cell for gene editing approaches.
Ø Identification of hematopoietic niches and how they are altered by aging and and malignant cells will allow us to develop strategies to improve hematopoiesis in the elderly and during leukemia treatment.
Lay Summary of Research.
Leukemias are sustained by immortal cells, called leukaemic stem cells. We will model genetic changes that occur in acute myeloid leukemia in mice, and identify the genes that are necessary for maintenance of the leukaemic stem cell with the aim of using these to develop new drugs to treat the disease. In addition we will investigate how normal blood cell formation is supported by the bone marrow environment, and how this support is disrupted by leukaemic cells and ageing, with the aim of developing therapies to improve general health of the aging population and the survival of leukemia patients during therapy. Finally, we will investigate the nature of the stem cells that maintain blood stem cell, and identify the changes these undergo during aging, in order to understand how stem cell aging contributes to age-dependent loss of immune function, and to develop ways to improve immunity in aged individuals.
All Publications Over the Past 5 Years.
Drissen R.#, N. Buza-Vidas#, E. Mancini, M. Lutteropp, A. Grover A, S.E.W. Jacobsen*, C. Nerlov*. 2014. Identification of two distinct pathways of myeloid lineage commitment. Submitted. (* and # Equal contribution).
Duarte S., N. Buza-Vidas, T. Bouriez-Jones, H. Ferry, A.J. Mead, P.S. Woll, D. Atkinson, U. Lendahl, C. Nerlov, and S.E.W. Jacobsen. 2014. Canonical Notch signaling is not required for steady state and emergency myeloerythropoiesis: Suppression of Notch target genes by RBP-Jĸ. Submitted.
Garcia-Silva S., D. Ruffell, S. Moore, A. Zay, M. Buono, D. Bilbao, V. Berno, J. Kim, O.W. Petersen and C. Nerlov. 2014. Identification of ductal- and alveolar-primed mammary luminal progenitors and regulation of the luminal transcriptional program by C/EBPβ. Submitted.
Matsuoka S., R. Facchini, K. Hosokawa, M. Buono, T. Luis, M. Lutteropp, T. Mizukami, A. Samraj, F. Arai, T. Suda, A. Mead, C. Nerlov* and S.E.W. Jacobsen*. 2014. Endothelial cell expression of the membrane bound form of Kit ligand defines bone marrow hematopoietic niches. Submitted. (* Equal contribution)
Woll P.S., U. Kjällquist, O. Chowdhury, H. Doolittle, D.C. Wedge, S. Thongjuea, R. Erlandsson, M. Ngara, K. Anderson, Q. Deng, A.J. Mead, L. Stenson, A. Giustacchini, S. Duarte, E. Giannoulatou, S. Taylor, M. Karimi, C. Scharenberg, T. Mortera-Blanco, I.C. Macaulay, S.A. Clark, I. Dybedal, D. Josefsen, P. Fenaux, P. Hokland, M.S. Holm, M. Cazzola, L. Malcovati, S. Tauro, D. Bowen, J. Boultwood, A. Pellagatti, J.E. Pimanda, A. Unnikrishnan, P. Vyas, G. Göhring, B. Schlegelberger, M. Tobiasson, G. Kvalheim, S.N. Constantinescu, C. Nerlov, L. Nilsson, P.J. Campbell, R. Sandberg, E. Papaemmanuil, E. Hellström-Lindberg, S. Linnarsson, S.E. Jacobsen. 2014. Myelodysplastic syndromes are propagated by rare and distinct human cancer stem cells in vivo. Cancer Cell 25:794-808.
Grover, A., E. Mancini, S. Moore, A. Mead, D. Atkinson, K.D. Rasmussen, D. O’Carroll, S.E.W. Jacobsen and C. Nerlov. 2014. Erythopoietin guides multipotent hematopoietic progenitor cells towards an erythroid fate. J. Exp. Med. 211: 181-8.
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/EBPα mutant Acute Myeloid Leukemia. Cancer Cell 24: 575-88.
Sanjuan-Pla A.,I. Macaulay, C.T. Jensen, P.S. Woll, T.C. Luis, A. Mead, S. Moore, C. Carella, T. Bouriez-Jones, O. Chowdhury, L. Stenson, M. Lutteropp, J.A.C. Green, R. Facchini, H. Boukarabila, A. Grover, A. Gambardella, J. Carrelha,P. Tarrant, D. Atkinson, S.-A. Clark, C. Nerlov* and S.E.W. Jacobsen*. 2013. Platelet-biased stem cells reside at the apex of the hematopoietic stem cell hierarchy. Nature, 502: 232-236. (* Equal contribution).
Kaveri D., P. Kastner, D. Dembélé, C. Nerlov, S. Chan and P. Kirstetter. 2013. -catenin activation synergizes with Pten loss and Myc overexpression in Notch-independent T-ALL. Blood, 122: 694-704.
Mead, A.J., S. Kharazi,D. Atkinson,Iain Macaulay,C. Pecquet,S. Loughran,M. Lutteropp,P. Woll,O. Chowdhury,S. Luc,N. Buza-Vidas,H. Ferry,S.-A. Clark,N. Goardon,P. Vyas,S.N. Constantinescu,E. Sitnicka,C. NerlovandS.E.W. Jacobsen. 2013. FLT3-ITDs Instruct a Myeloid Differentiation and Transformation Bias in Lymphomyeloid Multipotent Progenitors. Cell Reports, 3: 1766-76.
Buza-Vidas, N., V. Cismasiu, S. Moore, A.J. Mead, P.S. Woll, S. Luc, M. Lutteropp, T. Bouriez-Jones, D. Atkinson, D. O'Carroll, S.E.W. Jacobsen* and C. Nerlov*. 2012. Dicer is selectively important for the earliest stages of erythroid development. Blood, 120: 2412-6. (* Equal contribution).
Hasemann M.S, M.B. Schuster, A.-K. Frank, K. Theilgaard-Mönch, T.Å. Pedersen, C. Nerlov and B.T. Porse. 2012. Phosphorylation of Serine 248 of C/EBPα is dispensable for myelopoiesis, but its disruption leads to a biased lineage choice in ageing mice. PLoS One 7:e38841.
Bereshchenko O., E. Mancini, L. Luciani, A. Gambardella, C. Riccardi and C. Nerlov. 2012. Pontin is essential for murine hematopoietic stem cell survival. Hematologica, 97: 1291-4.
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).
Luc S., T. Mizukami, H. Boukarabila, I.C. Macaulay, N. Buza-Vidas, T. Bouriez-Jones, M. Lutteropp, P.S. Woll, A.J. Mead, S. Matsuoka, J. Brown, A. Hultquist, H. Ferr, K. Anderson, S. Duarte, D. Atkinson, S. Soneji, A. Domanski, A. Farley, A. Sanjuan-Pla, C. Carella, R. Patient, M. de Bruijn, T. Enver, C. Nerlov, C. Blackburn, I. Godin and S.E.W. Jacobsen. 2012. Conserved pre-thymic and thymic commitment steps in embryonic and postnatal hematopoiesis. Nature Immunology, 13: 412-9.
Chau YY, D. Brownstein, H. Mjoseng, W.C. Lee, N. Buza-Vidas, C. Nerlov, S.E. Jacobsen, P. Perry, R. Berry, A. Thornburn, D. Sexton, N. Morton, P. Hohenstein, E. Freyer, K. Samuel, R. van't Hof and N. Hastie. 2012. Acute multiple organ failure in adult mice deleted for the developmental regulator Wt1. PLoS Genetics, 7:e1002404
FOG-1 and GATA-1 act sequentially to specify definitive megakaryocytic and erythroid progenitors. 2012. Mancini E., A. Sanjuan-Pla, L. Luciani, S. Moore, A. Grover, A. Zay, K.D. Rasmussen, S. Luc, D. Bilbao, D. O’Carroll, S.E.W. Jacobsen and C. Nerlov. EMBO J., 31: 351-65.
Kharazi S., A.J. Mead, A. Hultquist, C. Böiers, S. Luc, N. Buza-Vidas, Z. Ma, H. Ferry, D. Atkinson, K. Reckzeh, K. Masson, J. Cammenga, L. Rönnstrand, F. Arai, T. Suda, C. Nerlov, E. Sitnicka, S.E.W. Jacobsen. 2011. Impact of gene dosage, loss of wild type allele and FLT3 ligand on Flt3-ITD induced myeloproliferation. Blood 118: 3613-3621.
Ermakova O., L. Piszczek, L. Luciani, F.M. Cavalli, T. Ferreira, D. Farley, S. Rizzo, R.C. Paolicelli, M. Al-Banchaabouchi, C. Nerlov, R. Moriggl, N.M. Luscombe, C. Gross. 2011. Sensitized phenotypic screening identifies gene dosage sensitive region on chromosome 11 that predisposes to disease in mice. EMBO Mol Med. 3:50-66
Nerlov, C. 2010. Transcriptional and translational control of C/EBPs: the case for "deep" genetics to understand physiological function. Bioessays 32: 680-6. Review.
Bereshchenko, O., E. Mancini, S.J. Moore, D. Bilbao, R. Mansson, S.E.W. Jacobsen, D. Bryder and C. Nerlov. 2009. Hematopoietic stem cell expansion preceedes the generation of committed myeloid leukemia initiating cells in C/EBPα mutant AML. Cancer Cell 16: 390-400.
Bröske, A.-M., L. Vockentanz, S. Kharazi, M. Huska, E. Mancini, M. Scheller, A. Enns, M. Prinz, R. Jaenisch, C. Nerlov, A. Leutz, M.A. Andrede-Navarro, S.E.W. Jacobsen and F. Rosenbauer. 2009. DNA methylation protects hematopoietic stem cell multipotency from myelo-erythroid differentiation. Nat. Genet. 41: 1207-15. Selected for Faculty of 1000.
Ruffell, D., F. Mourkioti, A. Gambardella, P. Kirstetter, R.G. Lopez, N. Rosenthal and C. Nerlov. 2009. A CREB-C/EBPβ cascade co-ordinates M2-specific macrophage gene expression and promotes muscle injury repair. Proc. Natl. Acad. Sci. 106:17475-80.
Lopez, R.G., S. Garcia-Silva, S.J. Moore, O. Bereschenko, A.B. Martinez-Cruz, O. Ermakova, E. Kurz, J.M. Paramio and C. Nerlov. 2009. C/EBPα and -β couple interfollicular keratinocyte proliferation arrest to commitment and terminal differentiation. Nat. Cell Biol. 11: 1181-1190. Selected for Faculty of 1000.
Nerlov C. 2009. Targeting a chronic problem: elimination of cancer stem cells in CML. EMBO J. 28:167-8. News and views.
Diella, F., S. Chabanis, K. Kuck, C. Chica, C. Ramu, C. Nerlov and T. Gibson. 2009. KEPE – a motif frequently superimposed on sumoylation sites in metazoan chromatin proteins and transcription factors. Bioinformatics 25: 1-5
Markers of Esteem
Honorary Award of 2002, Danish Society for Cancer Research.
Young Investigator Award of 2000, Danish Cancer Society.
Fulbright Scholarship, July 1991-December 1993.
Member of the Danish Medical Research Council (FSS), October 2009-present. From January 2011, member of the FSS Executive Committee.
Member of the Scientific Committee, Danish Cancer Research Foundation, 1999-2002 (2001-2002: Vice-chair).
Invited lectures at major international meetings.
International Society for Experimetal Hematology Annual Meeting (Montreal, 2014)
Acute Leukemias XIII annual meeting (Munich, 2013)
European Hematology Association (Amsterdam, 2012)
Nobel Symposium on Stem Cell Transplantation (Stockholm, 2012)
International Society for Experimental Hematology Annual Meeting: Plenary lecture (Vancouver, 2011)
Frontiers in Cancer Research, Karolinska Institute (Stockholm, 2011)
International Society for Stem Cell Research; speaker and session chair (San Francisco,
2010)
International Society for Experimetal Hematology Annual Meeting (Athens, 2009)
European Hematology Association (Copenhagen, 2009)
EMBO Runx protein workshop (Oxford, 2009)
Epitron workshop (Montenegro, 2009)
EuroStells Workshop on Stem Cell Niches (Barcelona, 2008)
Stem Cells and Cancer, Barcelona BioMed Conference (Barcelona, 2007)