Group leader: 

Claus Nerlov

Position: 

Professor of Stem Cell Biology; Associate Director; Theme leader Lineage and Cell Specification

Contact: 

cnerlov [at] staffmail [dot] ed [dot] ac [dot] uk

Aims
We are using mouse genetics to investigate the mechanisms that control self-renewal and differentiation of normal and cancerous stem cells in the hematopoietic system and epithelial tissues, including the epidermis and mammary gland.

Background
The maintenance of stem cell and the control of their differentiation is a complex and tightly regulated process. Based on extrinsic cues from the stem cell niche and other stromal cells regulatory molecules (cytokine and morphogen receptors, transcription factors) in the stem cell will act to decide whether the cell will divide, selfrenew, differentiate or undergo apoptosis. The balance of these processes is critical for the proper homeostasis of self-renewing tissues, and their disruption can lead to organ failure and cancer.

Our laboratory investigates the role of transcription factors in the maintenance of hematopoietic and epithelial tissues, during normal development and cancer.

Approaches and progress
The main approach of the laboratory is the genetic analysis of transcription factors through conditional knockout and knockin technology. In this manner we can accurately model genetic changes occurring in human cancer, and develop new strategies for cancer cell eradication.

Recently, we have created a model of human acute myeloid leukemia that is now being used to identify genes important for tumor maintenance. In addition, we are analysing the effects of oncogenic mutations on normal stem cells, and analysing the alteration in the cellular chromatin state associated with normal differentiation and cancer development.     

Selected publications

• Bereshchenko O, Mancini E, Moore SJ, Bilbao D, Mansson R, Jacobsen SEW, Bryder D, Nerlov C. 2009. Hematopoietic stem cell expansion preceedes the generation of committed myeloid leukemia initiating cells in C/EBPalpha mutant AML. Cancer Cell 16:390-400.
• Bröske A-M, Vockentanz L, Kharazi S, Huska M, Mancini E, Scheller M, Enns A, Prinz M, Jaenisch R, Nerlov C, Leutz A, Andrede-Navarro MA, Jacobsen SEW, Rosenbauer F. 2009. DNA methylation protects hematopoietic stem cell multipotency from myelo-erythroid differentiation. Nature Genetics 41:1207-1215.
• Ruffell D, Mourkioti F, Gambardella A, Kirstetter P, Lopez RG, Rosenthal N, Nerlov C. 2009. A CREB-C/EBPbeta cascade co-ordinates M2-specific macrophage gene expression and promotes muscle injury repair. Proc Natl Acad Sci 106:17475-17480.
• Lopez RG, Garcia-Silva S, Moore SJ, Bereschenko O, Martinez-Cruz AB, Ermakova O, Kurz E, Paramio JM, Nerlov C. 2009. C/EBPalpha and -beta couple interfollicular keratinocyte proliferation arrest to commitment and terminal differentiation. Nature Cell Biology 11:1181-1190.
• Nerlov C. 2009. Targeting a chronic problem: elimination of cancer stem cells in CML. EMBO J 28:167-168. News and views.
• Diella F, Chabanis S, Kuck K, Chica C, Ramu C, Nerlov C and Gibson T. 2009. KEPE - a motif frequently superimposed on sumoylation sites in metazoan chromatin proteins and transcription factors. Bioinformatics 25:1-5.
• Weischenfeldt J, Damgaard I, Bryder D, Theilgaard-Mönch K, Thoren L, Cilius-Nielsen F, Jacobsen SEW, Nerlov C and Porse BT. 2008. The Nonsense-mediated mRNA decay factor UPF2 is essential for maintaining hematopoietic stem and progenitor populations. Genes Dev 22:1381-1396.
• Nygren JM, Liuba K, Breitbach M, Stott S, Thorén L, Roell W, Geisen C, Sasse P, Kirik D, Björklund A, Nerlov C, Fleischmann BK, Jovinge S and Jacobsen SEW. 2008. Myeloid and lymphoid blood cell contribution to non-hematopoietic cell lineages through irradiation-induced heterotypic cell fusion. Nature Cell Biology 10:584-592.
• Kirstetter P, Schuster MB, Bereschenko O, Moore S, Dvinge H, Kurz E, Theilgaard-Mönch K, Månsson R, Pedersen TÅ, Pabst T, Schrock E, Porse BT, Jacobsen SEW, Bertone P, Tenen DG, Nerlov C. 2008. Modeling of C/EBPα mutant acute myeloid leukemia reveals a common expression signature of committed myeloid leukemia initiating cells. Cancer Cell 13:299-310.
• Nerlov C. 2008. C/EBPs: recipients of extracellular signals though proteome modulation. Curr. Opin Cell Biol 20:180-185.
• Hasemann MS, Damgaard I, Schuster MB, Theilgaard-Mönch K, Balle Sørensen A, Mrsic A, Krugers T, Ylstra B, Pedersen FS, Nerlov C and Porse BT. 2008. Mutation of C/EBPα predisposes to the development of myeloid leukemia in a retroviral mutagenesis screen. Blood 111:4309-4312.
• Nerlov C. 2007. The C/EBP family of transcription factors: A paradigm for interaction between differentiation and proliferation control. Trends Cell Biol 7:318-324. Review.
• Fujimoto T, Anderson K, Jacobsen SEW, Nishikawa S-I, Nerlov C. 2007. Cdk6 blocks myeloid differentiation by interfering with Runx1 DNA binding and Runx1-C/EBPα interaction. EMBO J 26:2361-2370.
• Pedersen TÅ, Bereshchenko O, Garcia-Silva S, Ermakova O, Kurz E, Mandrup S, Porse BT, Nerlov C. 2007. Distinct C/EBPα amino acid motifs regulate lipogenic and gluconeogenic gene expression in vivo. EMBO J 26:1081-1093.
• Kirstetter P, Anderson K, Porse BT, Jacobsen SEW & amp; Nerlov C. 2006. Activation of the canonical Wnt pathway leads to loss of hematopoietic stem cell repopulation and multilineage differentiation block. Nat Immunol 7:1048-1056.
• Porse BT, Pedersen TÅ, Hasemann MS, Schuster MB, Kirstetter P, Luedde T, Damgaard I, Kurz E, Schjerling C, Nerlov C. 2006. The proline histidine rich CDK2/CDK4 interaction region of C/EBPα is dispensable for C/EBPα-mediated growth regulation in vivo. Mol Cell Biol 26:1028-1037.
• Porse BT, Bryder D, Theilgaard-Mönch K, Hasemann MS, Anderson K, Damgaard I, Jacobsen SEW, Nerlov C. 2005. Loss of C/EBPα cell cycle control increases myeloid progenitor proliferation and transforms the neutrophil granulocyte lineage. J Exp Med 202:85-96.
• Nerlov C. 2004. C/EBPα mutations in acute myeloid leukaemias. Nat Rev Cancer 4:394-400. Review.

Funding
EU 6th Framework Programme
EU 7th Framework Programme
Medical Research Council (UK)
Cancer Research UK
Swedish Research Council