Team PUISSANT

Molecular Mechanisms of Acute Myeloid Leukemia Development

Using AML as a model, our group aims to elucidate the role of cellular metabolism in leukemic progression and treatment adaptation. We implement large-scale functional screening approaches in vivo to evaluate how metabolic and epigenetic levers dictate the capacity of leukemic blasts to progress towards malignancy and adapt to therapeutic constraints – independently of mutational variations and clonal heterogeneity.

AML arises from the complex accumulation of genetic and epigenetic alterations, frequently within the context of hematopoietic aging. To better understand the intratumoral diversity of leukemic cells, our team uses cutting-edge single-cell technologies to extend the definition of leukemic clones beyond genetics, integrating epigenetic and functional heterogeneity into their characterization.

To evaluate the prognostic and predictive value of these cellular states, we develop biomarkers of leukemic diversity within patient cohorts. We apply advanced bioinformatic and biostatistical methodologies to syngeneic mouse models, combined with deep sequencing of longitudinal patient samples (matched diagnosis/relapse). This approach allows us to map the evolutionary trajectories of leukemic clones from initiation through treatment resistance.

Ultimately, we will leverage these insights to identify adaptive dead ends, that transformed cells are forced into, which could be exploited for the development of innovative therapeutic strategies.

Current standards of care for newly diagnosed or refractory/relapsed AML rely heavily on patient clinical status and genetic risk stratification. However, only a fraction of these genetic mutations can be directly targeted by therapies. To address this limitation, we developed the RAINBOW platform, a high-throughput flow cytometry screening framework designed to discover or validate predictive biomarkers for existing therapies, including ex vivo drug sensitivity testing under niche-mimicking conditions. Ultimately, this axis aims to improve patient care pathways, identify novel drug repositioning strategies, and uncover drug combinations.

This translational project will be facilitated by collaboration with the ALFA cooperative group and the France Médecine Génomique program, enabling us to conduct preclinical and collaborative studies within the framework of multicenter clinical trials (Phases I–III).