Chromosomal translocation master genes, mouse models and experimental therapeutics

Abstract

Molecular biologists have elucidated general principles about chromosomal translocations by cloning oncogenes or fusion genes at chromosomal translocation junctions. These genes invariably encode intracellular proteins and in acute cancers, often involve transcription and developmental regulators, which are master regulators of cell fate (e.g. LMO2 which is involved in acute leukaemia). Chromosomal translocations are usually associated with speci®c cell types. The reason for this close association is under investigation using mouse models. We are trying to emulate the cell-speci®c consequences of chromosomal translocations in mice using homologous recombination in embryonic stem cells to generate de novo chromosomal translocations or to mimic the consequence of these translocations. In addition, chromosomal translocation genes and their products are important targets for therapy. We have designed new therapeutic strategies which include antigen-speci®c recruitment of endogenous cellular pathways to a ect cellular viability and a novel structured form of antisense to ablate the function of fusion mRNAs. We will evaluate these procedures in the mouse models of chromosomal translocations and the long term aim is to perfect rapid procedures for characterizing patient-speci®c chromosomal translocations to tailor therapy to individual patients. Oncogene (2001) 20, 5763 ± 5777.

The role of CALM–AF10 gene fusion in acute leukemia

“…Chromosomal translocations have been studied in mouse models using a variety of techniques including retroviral transduction and bone marrow transplantation as well as gene-targeting and transgenic approaches. [48][49][50] Recently, three groups have published reports that used mice to study CALM-AF10 leukemia; findings from each of these reports are summarized in Table 2.…”

“…40,44,45,47 Mouse models of CALM-AF10 leukemia Animal models have provided tractable systems to study a wide range of human diseases, including the recurrent chromosomal translocations involved in hematologic malignancies. 48 Given the shared physiology between mice and humans, the mouse has become a standard animal model used to study pathophysiology and explore novel therapeutic approaches. Chromosomal translocations have been studied in mouse models using a variety of techniques including retroviral transduction and bone marrow transplantation as well as gene-targeting and transgenic approaches.…”

Overexpression of NPM–ALK induces different types of malignant lymphomas in IL-9 transgenic mice

“…Chromosomal translocations play an important role in the pathogenesis of both lymphoproliferative disorders and solid tumours by creating hybrid genes that encode fusion proteins with oncogenic properties (Look, 1997;Rabbitts, 2001). Receptor tyrosine kinases (RTKs) are involved in the control of cell proliferation and differentiation, as well as malignant transformation.…”

Oncogènes et leucémies : historique et perspectives

“…La liste de ces remaniements peut être consultée dans l'Atlas of genetics and cytogenetics in oncology and haematology (http://www.infobiogen.fr/services/chromcancer). La plupart des inversions et des translocations récurrentes ont été caractérisées au niveau moléculaire (pour revue, voir [9][10][11][12]) et ces études ont permis la découverte de nouveaux oncogènes. Les principaux remaniements chromosomiques conduisant à l'expression de protéines oncogéniques dans les leucémies sont présentés dans le Tableau I.…”