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.

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 multiomic pathways including metabolomic dependencies associated with MRD in AML patients treated with AZA/VEN treatment. Existing methods allowing single-cell whole transcriptome analysis, transcript mutation annotation, intracellular epitope detection harbored by anti-apoptotic and metabolic proteins that are critical and rate-limiting in their representative pathways will be leveraged.

The researcher will characterize the multiomic adaptation of leukemic cells in the first days of AZA/VEN treatment and in MRD banked 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 developed by us, followed by in vivo validation in the Tet2-/- syngeneic model.

Host:

INSERM, Paris, France

Supervisors:

Dr. Alexandre Puissant, Prof. Raphael Itzykson 

Duration:

36 months, starting 1-5-2025

Profile doctoral candidate:

Master’s degree in life sciences, other (bio)medical sciences, or related, and practical experience in cell biology, molecular biology, and basic bioinformatics. 

In addition:

The researcher will intern at ORTEC (Zoetermeer, The Netherlands, supervision John Jacobs) to learn MRD assessment by multiparameter flow cytometry and to apply AI using this MRD flow cytometry data, and at the University of Sevilla (Sevilla, Spain, supervisor Simon Mende-Ferrer) to test the identified drugs in MRD co-cultured with mesenchymal stromal cells (MSCs).