The project aims to define a functional description of transcriptional and metabolic rewiring of transient and persistent therapy resistant and leukemia initiating cells, and identify novel therapeutic strategies based on evolutionary traps for AML MRD.
Multiomic and metabolomic characterization of AML residual disease after AZA/VEN treatment. The project aims to define a functional description of transcriptional and metabolic rewiring of transient and persistent therapy resistant leukemic cells, and identify novel therapeutic strategies based on evolutionary traps for AML MRD. There is an urgent need to identify biomarkers of resistance to azacitidine/venetoclax (AZA/VEN), the first line treatment for unfit AML patients. The researcher will search for transient and persistent transcriptional programs underwent by leukemia-regenerating cells in AML patients treated with AZA/VEN treatment.
Existing methods like CITE-Seq allowing single-cell whole transcriptome and proteome analysis with simultaneous transcript mutation annotation and intracellular epitope detection using a novel 10x genomics platform will be leveraged to investigate the genotype-specific metabolic and transcriptomic status of individual cells at the same time. The researcher will also use multiparametric flow cytometry to assess known and potential cellular mechanisms associated with AZA/VEN resistance such as metabolic reprogramming using SCENITHTM, a switch on the dependence of anti-apoptotic proteins, modulation of cellular senescence and regulation of the immune system. The researcher will characterize the multiomic adaptation of leukemic cells in the first days of AZA/VEN treatment and in MRD biobanked samples from the DREAM clinical trial (NCT06225128). Moreover, AZA/VEN resistance will be studied in AML PDX models and a mouse Tet2-/- syngeneic model. Finally, drugs directed to the identified metabolic/transcriptomic characteristics using the evolutionary trap approach will be validated using a niche-dependent AML culturing system, followed by in vivo validation in the Tet2-/- syngeneic model.
Host
INSERM, Paris, France
Supervisors
Dr. Alexandre Puissant and Prof. Raphael Itzykson
Doctoral Candidate