Deciphering oncogenic activity of RARA in acute promyelocytic leukemia
Internship title: Deciphering oncogenic activity of RARA in acute promyelocytic leukemia
Name: Leukemia molecular pathogenesis
Affiliation: INSERM U944-CNRS UMR 7212
Address: Institut de recherche Saint-Louis- Bât. Jean Bernard, 1 avenue Claude Vellefaux 75010 Paris
Name: Hugues de Thé
Phone number: 0153724440
Name: Marie-Claude Geoffroy/Hugues de Thé
Phone number: 0153724440
Subject Keywords: Leukemogenesis, transcriptional regulation, retinoic acid signaling, genome-wide analysis
Tools and methodologies: Whole-genome sequencing analysis, ChIP-Seq. , proteomic
Summary of lab’s interests: Our lab has a long-standing interest in acute promyelocytic leukemia (APL) in which leukemogenesis is driven by the promyelocytic leukemia (PML)-retinoic acid receptor α (PML-RARA) fusion protein. Mechanistically, PML-RARA is a potent transcriptional repressor that block myeloid differenciation and promotes PML nuclear bodies (NB) disruption, thus preventing p53-driven senescence of leukemic cells. Major contributions were done to elucidate the therapeutical effect of retinoic acid (RA) and arsenic trioxide (As), two drugs used in combination to induce PML-RARA degradation and PML NB reformation. It now remains to further understand how PML-RARA induces progenitor self-renewal, a critical step to expand the disease.
Project summary: Our project aims to address molecular mechanisms underlying the initiation of APL and notably how PML-RARA induces expansion of immature myeloid progenitors in the bone marrow. Interestingly, we and others have observed that RARA overexpression is sufficient to immortalize myeloid progenitors ex vivo in cytokine-rich methyl cellulose and this, independently of PML. RARA, in association with retinoid X receptor alpha (RXRA) binds DNA on specific responsive elements to interfere on gene expression programs. We are currently using a genome-wide ChIP-seq approach to compare RARA mutants harbouring different binding affinities for DNA or retinoic acid, including those observed in RA-resistant patients. This will allow us to define RARA target genes that are critical for progenitor self-renewal. Furthermore, we aim to identify by mass spect analysis physical partners of PML-RARA necessary to the blockage or the reinitiation of myeloid differenciation upon RA/As treatment in an APL mouse model. Understanding the contribution of RARA in immortalization is particularly relevant in the field of carcinogenesis, since RARA has been recently implicated in other types of cancers. This could open the possibility to extend the use of retinoic acid in non-APL malignancies.
Interdisciplinary aspect of the project: This project will combined basic technics in cell culture, biochemistry and bio-informatic tools. Depending on his skills, internship will be involved in either one or both projects.