Our group has to major research interests: To provide a better understanding of the role of transcription factors in normal and malignant hematopoiesis and to characterize the importance of nonsense-mediated mRNA decay (NMD) in vivo.
Our research is centered on using mouse genetics to address basic biological problems.
1) Transcription factors in normal and malignant hematopoiesis
Normal hematopoiesis is a highly regulated process, which to a large extent is orchestrated by transcription factors that regulated lineage commitment events and establish lineage-specific gene expression programs. Conversely, interference with the functional properties of these transcription factors are often identified as the underlying cause of leukemia.
Previous studies have demonstrated the tumour suppressor function of the transcription factor C/EBPa. In order to gain further insights into the role of C/EBPa in myeloid leukemia, we have used retroviral insertional mutagenesis to identify novel oncogenes that collaborate with a mutant form of C/EBPa in leukemogenesis. Current and future efforts are aimed at functionally validating the oncogenic properties of these genes. Our hope is that this research will uncover novel targets for therapeutic intervention.
NMD is an elaborate RNA surveillance system that rids the eukaryotic cell from mRNAs containing premature termination codons (PTC). Such transcripts may arise from mutational events, faulty splicing, expression of pseudogenes as well as through genomic rearrangement processes occurring during lymphocyte development.
Although the mechanistics of NMD have been studied in great detail in tissue culture cells, very little is known about the importance of NMD for mammalian development and tissue homeostasis. To address this issue, we are analyzing mouse knockout lines of key NMD components.
Thoren LA, Nørgaard GA, Weischenfeldt J, Waage J, Jakobsen JS, Damgaard I, Bergström FC, Blom AM, Borup R, Bisgaard HC, Porse BT. UPF2 is a critical regulator of liver development, function and regeneration. PLoS One. 2010 Jul 19;5(7):e11650.
Marstrand TT, Borup R, Willer A, Borregaard N, Sandelin A, Porse BT, Theilgaard-Mönch K. A conceptual framework for the identification of candidate drugs and drug targets in acute promyelocytic leukemia. Leukemia. 2010 Jul;24(7):1265-75. Epub 2010 May 27.
Weischenfeldt J, Damgaard I, Bryder D, Theilgaard-Mönch K, Thoren LA, Nielsen FC, Jacobsen SE, Nerlov C and Porse BT (2008). NMD is essential for hematopoietic stem and progenitor cells and for eliminating by-products of programmed DNA rearrangements. Genes Dev., 22, 1381-1396.
Kirstetter P, Schuster MB, Bereshchenko O, Moore S, Dvinge H, Kurz E, Theilgaard-Mönch, K, Månsson, R, Pedersen TÅ, Pabst T, Schröck E, Porse BT, Jacobsen, SEW, Bertone, P, Tenen DG and Nerlov C (2008). Modelling of C/EBPa mutant acute myeloid leukaemia reveals a common expression signature of committed myeloid leukaemia initiating cells. Cancer Cell, 13, 299-310.
Hasemann MS, Damgaard I, Schuster MB, Theilgaard-Mönch K, Sørensen AB, Mrsic A, Krugers T, Ylstra B, Pedersen FS, Nerlov C and Porse BT (2008). A retroviral insertional mutagenesis screen in a Cebpa mutant background. Blood, 111, 4309-4321.
Kirstetter P, Anderson K, Porse BT, Jacobsen SE and 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, Bryder D, Theilgaard-Mönch K, Hasemann MS, Anderson K, Damgaard I, Jacobsen SE and Nerlov C (2005). Loss of C/EBPa cell cycle control increases myeloid progenitor proliferation and transforms the neutrophil granulocyte lineage. J. Exp. Med. 202, 85-96.