Used with success for treating acute promyelocytic leukemias, retinoic acid and arsenic oxide induce the differentiation of malignant cells. Is this differentiation responsible for the eradication of the disease? Researchers from a CNRS / Université Paris Diderot unit, working in the Hôpital Saint-Louis in Paris, have managed to prove that this is not the case: the remissions are above all linked to the disappearance of the malignant stem cells responsible for the leukemia.
Professor Hugues de Thé's team has recently demonstrated that this disappearance, induced by the treatment, is caused by the specific degradation of the protein responsible for the pathology. This therapeutic targeting constitutes a promising way forward that could be extended to other types of leukemia. Supported by the Ligue Contre le Cancer and by the Institut National du Cancer, this work was published on 23 November on the website of the journal Nature Medicine.
Acute promyelocytic leukemia (APL) is characterized by an excess of immature and malignant cells. This rare form of leukemia is the consequence of a chromosome translocation, uniquely found in leukemic cells. This chromosomal anomaly leads to the production of a fusion protein known as PML-RAR. Stemming from PML(1) and RAR(2) genes, this fusion protein is at the root of the pathology. It blocks the differentiation of promyelocytes, which remain immature. Incapable of disappearing naturally, the malignant cells accumulate in the bone marrow and in the blood.
At the moment there are two agents that are particularly effective for treating APL: a hormone, retinoic acid, and a poison, arsenic oxide. In use for a number of years altready, they bring about remission in patients. Until now, this success has been explained by the fact that these drugs induced differentiation of the malignant cells into normal differentiated cells, which end up dying, which results in the normalization of the condition of the bone marrow. But can this differentiation explain the recoveries?
By modeling the response of these two agents, the team headed by Hugues de Thé(3) has partially answered this question. The researchers have for instance shown that the treatment of APL with these medicines brings about not only the differentiation of leukemic cells but, above all, the disappearance of the malignant stem cells responsible for the leukemia. This eradication is caused by the degradation of the fusion protein PML-RAR, itself induced by the cooperative action of the two drugs. Targeting the destruction of this protein is therefore a favored strategy for destroying leukemic stem cells.
This work represents a remarkable example of therapeutic targeting of a protein responsible for a cancer. It demonstrates that it is possible to specifically destroy cancerous stem cells by inducing the degradation of the proteins responsible for their survival. This new concept could be extended to other types of leukemia.
- PML for promyelocytic leukaemia, which modulates cell multiplication and cell death.
- RAR for retinoic acid receptor, which modulates the granular white blood cell differentiation program.
- Director of the “Molecular pathology and virology” research unit (CNRS / Université Paris Diderot) and Professor at the Hôpital St. Louis, AP/HP, Paris.
- Rihab Nasr, Marie-Claude Guillemin, Omar Ferhi, Hassan Soilihi, Laurent Peres, Caroline Berthier, Philippe Rousselot, Macarena Robledo-Sarmiento, Valérie Lallemand-Breitenbach, Bernard Gourmel, Dominique Vitoux, Pier Paolo Pandolfi, Cécile Rochetteegly, Jun Zhu & Hugues de Thé. APL leukemia initiating cell eradication through cooperative cAMPRA-and arsenic-triggered PML/RARA degradation. Nature Medicine, 23 November 2008
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