Differentiation therapy of human leukemia

L Degos, MD

Institut Universitaire dHématologie, Hopital St Louis, AP-HP - Paris - France

Malignancies are characterized by three major clonal cellular disorders : an arrest of cell differentiation (presence of immature cells), an inhibition of apoptosis (accumulation of cells) and an accelerated multiplication (proliferation of cells). The three impairements are partly linked. In fact using cell line cultures, induction of differentiation restores a natural cell death program and inhibits the excessive proliferation. Therefore, the engagement of malignant cells into the maturation pathway, so called differentiation therapy, induces progressively an apparent normal cell life. Combinations of inducers of differentiation with proapoptotic agents and antiproliferative drugs will play a major role in the future treatment of cancers. Leo Sachs (Weitzmann Institute, Israël) was the first who demonstrated that a malignancy is not an irreversible state, showing that it is possible to circumvent the genetic defects either in vitro (cell line culture) using differentiating agents or in vivo (graft of leukemic cells in mice embryos). Acute promyelocytic leukemia (APL) treated by all trans retinoic acid (ATRA) is the first model of a human malignant disease reverted by a differentiating agent. APL is also the first model of an acquired genetic disease specifically treated by a drug (ATRA) APL is characterized by the translocation (15 ;17) with a fusion of a large part of the retinoic acid receptor alpha gene (RARa) on chromosome 17 to a part of the promyelocytic leukemia (PML) gene on chromosome 15. A pharmacologic dose of ATRA overcomes the blockage of exchange between corepressors and coactivators caused by the fusion protein PML-RARa. Other cell modifiers targeted on oncogenic events are actually proposed in leukemia such as arsenic inducing cell apoptosis in APL, and antikinases inhibiting the cell multiplication which have shown promising results in chronic myeloid leukemia. Thus two drugs (ATRA and arsenic) are now available for the treatment of APL. These two drugs have different mechanism of action : ATRA acts on RARa gene product and reverses the differentiation arrest ; Arsenic acts on PML gene product and restores the cell death program. In mice, transplanted with cells bearing the PLM-RAR transgene, the induced leukemia is cured definitely by the association of ATRA and arsenic. The malignant cells seem to be more sensitive to differentiation and apoptotic treatment when the intra cellular concentration of cAMP is increased. Some trials are actually on going associating ATRA, arsenic and cAMP inducers. More over differentiating agents could act when DNA is not attached to histones. Thus histone deacetylase inhibitors facilitates the transcription of gene targetted by differentiating agents. Therefore treatments combining differentiating agents, cAMP inducers and histone deacetylase inhibitors are also actually tested. In conclusion, differentiation therapy opened a new era of treatment of cancer. Other cell modifiers targetted on oncogenic event inducing apoptosis, or inhibiting a proliferative signal are now available. Thus cancer will be cured by tailored treatment adapted to the oncogenic events.

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Paper presented at the International Symposium on Predictive Oncology and Intervention Strategies; Paris, France; February 9 - 12, 2002; in the section on Novel Molecular Therapies.