Descripción del proyecto
Comprender la alteración de los cuerpos nucleares de leucemia promielocítica en el marco del tratamiento de la leucemia mielógena aguda
Conocer mejor la manifestación y el desarrollo de la leucemia mielógena aguda (LMA o AML, por sus siglas en inglés) puede dar lugar a nuevas estrategias terapéuticas. La leucemia promielocítica aguda (LPA o APL, por sus siglas en inglés), un subtipo de LMA, se puede curar con éxito mediante politerapia. Por consiguiente, la comprensión de los mecanismos subyacentes a la patogenia y el éxito en el tratamiento de la LPA mejorará el tratamiento de los subtipos de LMA con un mal pronóstico. Los cuerpos nucleares de leucemia promielocítica, un arquetipo de orgánulos sin membrana que concentran proteínas en zonas diferenciadas del nucleoplasma, son esenciales para la patogenia de la LPA y la respuesta al tratamiento. El proyecto financiado con fondos europeos PMLingAML dilucidará los mecanismos de la alteración de los cuerpos nucleares de leucemia promielocítica en la LPA con el fin de aplicar estos conocimientos en el tratamiento de otros subgrupos de LMA.
Objetivo
Understanding the initiation and development of acute myeloid leukemia (AML) represents an important challenge which may lead to the identification of new therapeutic strategies. Acute promyelocytic leukemia (APL) was formerly the most lethal subset of AML; however, today the vast majority of APL patients can be cured by combination therapy. Therefore, fully understanding the mechanisms underlying successful treatment, by analysing the biology of APL pathogenesis will assuredly improve the management of AML subsets associated with a poor outcome, such as NPM1-mutated AML. Using a novel knock-in mouse model, PmlC62A/C65A, which mimics Pml nuclear body (NB) disruption induced by the main oncoprotein PML-RARα in APL, we have previously shown that Pml NBs are essential in APL pathogenesis and treatment response. Our project “PMLingAML” aims to carry on elucidating the impact of Pml NB disruption in APL, and then to apply this knowledge in other AML subsets. To this end, a mass spectrometry analysis will be conducted on both hematopoietic stem and progenitor (LSK) cells and promyelocytes isolated from healthy and leukemic murine bone marrows, to decipher the consequences of Pml NB disruption on the SUMOylome. Next, since PML NBs and NPM1 share common cellular functions and characteristics, we will analyse the inter-relationship between them; their localisation and dynamics will be assessed according to their respective status (disruption, mutation, knock-out), for example by high resolution imaging, both in various healthy and leukemic mouse models (incl NPM1c+ and NPM1c+/FLT3ITD), and in patient samples. Their respective roles in response to a drug under clinical trial, Dactinomycin, will also be scrutinised. Finally, as DNA damage repair is an important function disrupted during leukemogenesis, the roles of Pml NBs and Npm1 will be assessed together with their inter-relationship, with particular focus on the base excision repair (BER) pathway.
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MSCA-IF - Marie Skłodowska-Curie Individual Fellowships (IF)Coordinador
75654 Paris
Francia