Group leader: Peter Marynen

PhD: Univ. of Leuven, Leuven, Belgium, '84
Postdoc: Stanford Univ. Medical School, California, USA, '84-'86
1995-2009 VIB Group leader
2005-2009 Research director, group Biomedical Sciences, K.U.Leuven
Vice rector of Research Policy, K.U.Leuven since August 2009

Sr. academic staff: Guy Froyen

PhD: Rega Institute, Univ. of Leuven, Leuven, Belgium, ‘92
Postdoc: Univ. of Leuven, Leuven, Belgium, ’92-‘97
1997-2000 Staff Scientist, Janssen Pharmaceutica, Beerse Belgium
Since 2000 VIB Project leader, Univ. of Leuven
Since 2006 Associate professor, Univ. of Leuven

Within the human genome laboratory, Guy Froyen is supervising a group investigating X-chromosomal disorders. Visit the page of this group to find out more information: Group for the Research of X-chromosomal Disorders

Research interests

The mission of the Human Genome Laboratory is to detect, characterize and treat clinically important mutations. The strategy of the group is based on the mining of the unique patient material available through our collaboration with the clinical groups of the Center for Human Genetics, KULeuven.
This group focuses on three different lines of investigations. The first aims at the characterization of molecular processes involved in the genesis and evolution of cancer. The second at the identification of genes or mechanisms involved in the pathogenesis of intellectual disability (ID). The third aims at the development and study of chromosomal vectors for transgenesis. All strategies originate from the identification of aberrations in chromosomes in constitutional or acquired disease, depend on the use of a common ‘genomics’ toolkit, and use extensively the resources provided by the Human Genome Project.

1. The characterization of the mutated genes in malignancies provides important insights in the process of aberrant growth and differentiation, but is also instrumental for the clinical management of these diseases by allowing a stratification of the patient population improving the choice of therapeutic strategies and by defining molecular targets for the rational design of anticancer drugs. We focus on new genes, recurrently involved in defining specific disease entities and novel mechanisms leading to the formation of fusion oncogenes. The API-2-MLT fusion is marker for gastric MALT-type lymphoma resistant to H. pylori eradication and defines a novel pathway for NFkB activation. The characterisation of the EWSR1-CIZ and TAF15-CIZ fusions implicate a role of the transcription factor CIZ in (aberrant) hematoposiesis and can lead to insights in the role of EWSR1/TAF15/FUS in oncogenesis. The FIP1L1-PDGFRA fusion is found is about 40% of the ideopatic eosinophila cases, showing that this is a clonal disease and a target for kinase inhibitors. Together with the NUP214-ABL1 fusion, present in 7% of T-ALL, this is a prime example of novel cryptic chromosomal anomalies involved in oncogene formation.
   This project is headed by Thijs Baens. Key references 1-5.
2. As part of the Euro-MRX consortium (http://www.euromrx.com/en/links.html#) our group has significantly contributed to the identification of genes involved in intellectual disability (ID).  The mutations of known ID genes explains approximately 50% of all XLID, hence a large number of ID genes have yet to be discovered. Our group has been instrumental in detecting causal copy number gains (duplications) on the X chromosome resulting in ‘too much’ expression of particular genes leading to ID. These data clearly demonstrate that not only loss of function but also increased gene dosage is harmful for normal cognitive development and potential associated clinical characteristics. With the current technological improvements we are currently perform exome or even whole genome sequencing to identify disease-associated mutations. Finally we are investigating the contribution of epigenetic alterations in cognitive disorders through ChIP-chip and ChIP-seq.It is the general aim of this project to identify and characterize new ID genes or mechanisms. We anticipate that these genes will provide new insights in the molecular, cellular and biological processes involved in central nervous system physiology in general and in normal cognitive functions in particular. This project is headed by Guy Froyen (website). Key references 6-10.
3. In the field of transgenesis it is our general aim to develop a chromosomal vector. The system consists of a minichromosome carrying (a) selectable marker(s), and allowing the directed introduction of foreign DNA fragments (PACs/BACs) to generate transchromosomal mice. Proof-of-principle was provided for the use of this system for the generation of cell lines and mice with stable, regulated and predictable expression of transgenes. Key references 11-12.

Key Publications 

1. Rosebeck S., Madden L., Jin X., Gu S., Apel I.J., Appert A., Hamoudi R.A., Noels H., Sagaert X., Van L.P. et.al. (2011). Cleavage of NIK by the API2-MALT1 fusion oncoprotein leads to noncanonical NF-kappaB activation. Science 331:468-472.
2. Noels H., Somers R., Liu H., Ye H., Du M.Q., De Wolf-Peeters C., Marynen P., Baens M. (2009). Auto-ubiquitination-induced degradation of MALT1-API2 prevents BCL10 destabilization in t(11;18)(q21;q21)-positive MALT lymphoma. PLoS. ONE. 4:e4822-.
3. Coornaert B., Baens M., Heyninck K., Bekaert T., Haegman M., Staal J., Sun L., Chen Z.J., Marynen P., Beyaert R. (2008). T cell antigen receptor stimulation induces MALT1 paracaspase-mediated cleavage of the NF-kappaB inhibitor A20. Nat. Immunol. 9:263-271.
4. Noels H., van L.G., Hagens S., Broeckx V., Beyaert R., Marynen P., Baens M. (2007). A Novel TRAF6 binding site in MALT1 defines distinct mechanisms of NF-kappaB activation by API2middle dotMALT1 fusions. J. Biol. Chem. 282:10180-10189.
5. Baens M., Fevery S., Sagaert X., Noels H., Hagens S., Broeckx V., Billiau A.D., De Wolf-Peeters C., Marynen P. (2006). Selective expansion of marginal zone B cells in Emicro-API2-MALT1 mice is linked to enhanced IkappaB kinase gamma polyubiquitination. Cancer Res. 66:5270-5277.
6. Vandewalle J., Van Esch H., Govaerts K., Verbeeck J., Zweier C., Madrigal I., Mila M., Pijkels E., Fernandez I., Kohlhase J. et.al. (2009). Dosage-dependent severity of the phenotype in patients with mental retardation due to a recurrent copy-number gain at Xq28 mediated by an unusual recombination. Am. J. Hum. Genet. 85:809-822.
7. Froyen G., Corbett M., Vandewalle J., Jarvela I., Lawrence O., Meldrum C., Bauters M., Govaerts K., Vandeleur L., Van Esch H. et.al. (2008). Submicroscopic duplications of the hydroxysteroid dehydrogenase HSD17B10 and the E3 ubiquitin ligase HUWE1 are associated with mental retardation. Am. J. Hum. Genet. 82:432-443.
8. Bauters M., Van Esch H., Friez M.J., Boespflug-Tanguy O., Zenker M., Vianna-Morgante A.M., Rosenberg C., Ignatius J., Raynaud M., Hollanders K. et.al. (2008). Nonrecurrent MECP2 duplications mediated by genomic architecture-driven DNA breaks and break-induced replication repair. Genome Res. 18:847-858.
9. Froyen G., Van Esch H., Bauters M., Hollanders K., Frints S.G., Vermeesch J.R., Devriendt K., Fryns J.P., Marynen P. (2007). Detection of genomic copy number changes in patients with idiopathic mental retardation by high-resolution X-array-CGH: important role for increased gene dosage of XLMR genes. Hum. Mutat. 28:1034-1042.
10. Van Esch H., Bauters M., Ignatius J., Jansen M., Raynaud M., Hollanders K., Lugtenberg D., Bienvenu T., Jensen L.R., Gécz J. et.al. (2005). Duplication of the MECP2 Region Is a Frequent Cause of Severe Mental Retardation and Progressive Neurological Symptoms in Males. Am. J. Hum. Genet. 77:442-453.
11. Voet T., Schoenmakers E., Carpentier S., Labaere C., Marynen P. (2003). Controlled transgene dosage and PAC-mediated transgenesis in mice using a chromosomal vector. Genomics 82:596-605.
12. Voet T., Vermeesch J., Carens A., Durr J., Labaere C., Duhamel H., David G., Marynen P. (2001). Efficient male and female germline transmission of a human chromosomal vector in mice. Genome Res. 11:124-136.
    
     

Visit the homepage of the laboratory

Research team