The aim of this project is to get a deep understanding of the mechanisms that drive senescence post chemotherapy and of senescence-induced halting of AML proliferation and modulation of immune-mediated clearance.

Moreover, as persistent, senescent AML MRD cells may generate an inflammatory milieu contributing to escape from treatment and immune-clearance the researcher is expected to find several therapeutic strategies to enhance immune-mediated elimination of AML MRD cells. The researcher will define a molecular blueprint of senescence establishment and its effects on immune-mediated clearance by elucidating the effect of senescent residual AML cells on the inflammatory niche and the activity of T cells, macrophages and NK cells.

The researcher will use the “organ on chip” 3D models and AML PDX mouse models to generate MRD after chemotherapy. Then naïve diagnosis and residual leukemia cells (MRD) with low and high senescence-associated secretory phenotype (SASP), together with the immune-microenvironment will be purified and characterized by scRNA sequencing.

The functional effect of senescent AML MRD on various immune cell populations, such as T cells, NK cells and macrophages will be studied by mixed AML and lymphocyte and NK cell cultures.  Based on the obtained data, the researcher will devise (immune) therapies and/or enhance immune cell activity that will eliminate MRD.

Host:

Ospedale San Raffaele, Milan, Italy

Supervisor:

Dr. Raffaella DiMicco 

Duration:

36 months, starting 1 – 5 - 2025, and extendable up to 48 months if allowed by the regulations of the Ph.D program at the host institution.

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 Amsterdam UMC (The Netherlands, 2 months, supervisor Dr. Linda Smit) to generate ex vivo MRD and in the AML PDX xenograft model, and study senescence post treatment, and an intern in the team of Marion Subklewe at the University Hospital München (3 months, Germany) to investigate efficacy of senescent-associated characteristics as immune stimulatory therapies.