Facteurs épigénétiques dans l’hématopoïèse normale et pathologique

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CRCM PhD Day 2021 will take place on May 28 2021 - Les mitochondries nouvelles cibles thérapeutiques potentielles dans le cancer du pancréas - La cycline A2, qui maintient l'homéostasie du côlon, est un facteur de pronostic dans le cancer colorectal -

The main scientific objective of the team is to decipher the transcriptional networks involved in the regulation of proliferation versus differentiation of normal or pathological hematopoietic cells. We are interested in the epigenetic mechanisms related to age-related deregulation of hematopoiesis. In parallel, we develop a more applied research in collaboration with the clinicians of the Paoli-Calmettes Institute, using epigenomics for AML, in order to improve its management. Altogether, our scientific activity is mainly focused on the following keywords: acute myeloid leukemia, hematopoietic stem cell, epigenetics, aging, gene expression.

Nos approches expérimentales
Epigenetics, PLZF and HSC aging

The hematopoietic system deteriorates with age and numerous changes occurring in both humans and mice have been reported, including reduced production of red blood cells and lymphocytes as well as a relative increase in the production of myeloid cells. This results in a reduction in the number of adaptive immune cells that promotes immune-senescence and an increase in acute myeloid leukemia. Emerging evidence indicates that these alterations come from changes in the biological properties of the pool of aging hematopoietic stem cells (HSCs).

We investigate (de)regulated epigenetic pathways involved in the fate of HSCs using mouse models and single cell RNA-seq approaches.

  • We showed that aging affects HSC cell cycle regulation and HSC pool composition
  • We showed that the transcription and epigenetic factor PLZF (promyelocytic zing finger), involved in leukemogenesis, plays an important role in the regulation of the cycle and function of HSCs in relation to aging.

As chromatin changes are actors in the aging of HSCs, we are complementing transcriptomic studies with chromatin omics approaches (scATAC-seq). We propose to validate the new highlighted actors of hematopoietic aging, using invalidated mouse models or by overexpressing new potentially interesting signaling pathways.

Integrating the data will provide a complete map of changes that occur in HSC throughout life of individuals and will help understanding the chromatin implication of physiological changes and assess how chromatin modifications are linked to clonal evolution of HSCs and leukemia predisposition during aging.

Epigenetics deregulation in acute myeloid leukemia

We are studying of epigenetic alteration referenced as H3K27me3 HIST1high, discovered in the laboratory and affecting CN-AML. Our results suggest that the regulation of histone genes by H3K27me3 influences the evolution of CN-AML and response to treatment. We are studying the role of this new epigenetic anomaly in the evolution of the CN-AML mutated for NPM1 by developing different axes. We are studying the consequences of the presence of H3K27me3HIST1high and the subsequent decrease in histone gene expression in the progression of NPM1mut CN-AML and its sensitivity to chemotherapy. We Test the effect of potentially interesting (epi)drugs in AML on H3K27me3HIST1 status. We are assessing NPM1mut CN-AML heterogeneity regarding H3K27me3HIST1high status and evolution after chemotherapy.

This project will benefit from cellular models modified in their epigenome, patient-derived xenograft mouse models, access to new epidrugs and single cell approaches. It will provide a better understanding of epigenetic deregulations in AMLs and, in the long term, define new therapeutic strategies.