Identification, characterization and analysis of the molecular consequences of mutant protein tyrosine kinase and related genes in leukaemia and lymphoma.

Cancer cells are characterized by uncontrolled cell growth, invasion and the ability to metastasize. These characterisitics are driven by an aberrant expression of proteins involved in several signal transduction pathways implicated in cell proliferation, apoptosis, differentiation, etc. One group of proteins implicated in tumorigenesis is the family of protein tyrosine kinases (PTKs). As constitutively activated PTKs are essential for the survival of cancer cells, they are key targets for inhibitors used to treat these tumours. Using cytogenetic and molecular techniques, we identified and characterized two novel PTK-associated fusion genes in human lymphoma, i.e. the SEC31A-JAK2 fusion involving the Janus kinase 2 (JAK2) tyrosine kinase gene at 9p24, and the SEC31A-ALK fusion involving the anaplastic lymphoma kinase (ALK) tyrosine kinase gene at 2p23. We are now attempting to unravel the mechanism by which the fusion proteins mediate constitutive kinase activation and test their sensitivity to inhibition by small molecule inhibitors and small interfering RNA (siRNA) both in vitro in cell lines and in vivo in bone marrow transplant mouse models. In addition, we found two other genes at 9p24, programmed death ligand (PDL) 1 and 2, to be targeted by chromosomal translocations and overexpressed in some lymphomas, and a cryptic 9p24 deletion in a variety of B-cell neoplasms. The consequences of PDL1/2 overexpression in vitro and the consequences of the cryptic 9p24 microdeletion in patient material and cell lines are currently investigated.

Keywords:JAK2, ALK, Lymphoma, Chimeric fusion, Oncogene, Chromosomal translocation, Tyrosine kinase, Leukemia

Disciplines:Genetics, Systems biology, Molecular and cell biology