Oncogènes et leucémies: historique et perspectives Oncogenes in leukemia: historical background and therapeutic prospect

Résumé

Les leucémies sont des maladies clonales et acquises de la cellule souche hématopoïétique ou d’un précurseur déjà commis vers les lignées lymphoïde et/ou myéloïde. Leur classification repose sur des critères morphologiques, l’expression de marqueurs membranaires, et pour les leucémies lymphoïdes, l’étude des réarrangements des gènes du récepteur T ou d’immunoglobulines qui permettent de caractériser le stade de différenciation des cellules leucémiques. Le clonage moléculaire de remaniements chromosomiques récurrents a permis d’identifier de nombreuses altérations géniques qui constituent des outils diagnostiques et de suivi thérapeutique maintenant pris en compte dans les nouveaux critères de classification des leucémies. Le développement récent de thérapeutiques ciblées sur l’activité ou la stabilité d’une protéine oncogénique a été récemment illustré par les succès thérapeutiques obtenus dans le traitement des leucémies aiguës promyélocytaires et de la leucémie myéloïde chronique.

Summary

Oncogenes involved in the development of hematological malignancies were first discovered through the study of experimental leukemias induced in animals by retroviruses. The discovery that some of these genes were located at the breackpoints of chromosome rearrangements in human malignancies, such as the MYC gene in Burkitt’s lymphoma and the ABL gene in chronic myeloid leukemia (CML) has suggested that chromosome abnormalities were causally implicated in the pathogenesis of human diseases. Numerous nonrandom somatically acquired chromosomal translocations or inversions have been identified in human leukemias. The molecular cloning of the genes located at the breakpoints of these rearrangements allowed to identify more than 100 new oncogenes, the products of which affect normal programs of cell proliferation, differentiation and survival. Chromosome translocations can lead to the deregulated expression of a normal gene product, but in most cases of leukemia, chromosome rearrangements result in the expression of a chimeric fusion protein. Oncogene products associated with acute leukemias are often transcription factors while tyrosine kinases and antiapoptotic proteins are more commonly activated or overexpressed in chronic leukemias and in lymphomas. Recent data indicated that gene rearrangements were not the sole gene alterations occurring in human leukemia since point mutations could also affect the function of transcription factors playing a key role in hematopoiesis such as C/EBPα, GATA1 and AML1. But the most exciting finding was the discovery of activating point mutations in tyrosine kinase receptors such as FLT3 and c-KIT in acute leukemia. Treatment of leukemia could therefore benefit from new therapeutic approaches targeting the function of specific oncogene products as already demonstrated for CML and acute promyelocytic leukemia.