PhD thesis position : Therapeutic targets in leukemia in preclinical models

Thesis offer - 3-year funding

We are looking for a highly motivated candidate to work on the function and inhibition of therapeutic targets in leukemia in preclinical models. The focus of the project is on the role of the protein kinase CDK6 in acute myeloid leukemia.

Project description

Cyclin-dependent kinase 6 (CDK6) is crucial regulator of highly aggressive acute myeloid leukemia (AML) and a recognized therapeutic target. Understanding the mechanisms initiated by CDK6 inhibition is essential to reveal therapeutic windows enabling novel combinatorial treatment strategies. We propose to clarify the mechanism by which CDK6 regulates vesicle biogenesis and function and in turn the microenvironment. We will investigate whether the combination of CDK6 inhibitors with drugs targeting vesicle regulation can benefit AML patients.

We will take advantage of existing CDK4/6 kinase inhibitors and genetically modified cell models expressing a CDK6 mutant. We will define how CDK6 regulates vesicle biogenesis and fucntion via transcriptional regulation and protein interaction by integrating ChIP-Seq, transcriptomic and phospho-proteomic data. We will get deeper insights if CDK6 inhibition changes the AML-EV cargo and if these changes effect leukemic niche cells, by establishing a 3D model with stromal, endothelial and healthy hematopoietic cells with AML-EVs. In this model, cells will be characterized through phenotypical and functional assays and the transcriptomic pattern will be determined by RNA-Seq. A combinatorial drug screen with CDK6 inhibitors and small molecules targeting vesicle biogenesis and function will be implemented to investigate novel therapeutic strategies.

Methods will include cytometry, functional assays, RNA-Seq, western, transduction with virus vectors, RNAi; qPCR, bioinformatic analysis. AML models: primary patient cells, cell lines, normal HSPC, mouse models of AML.

Contact 

Paulo DE SEPULVEDA, Head of the Signaling and Hematopoiesis Lab

Centre de Recherche en Cancerologie de Marseille (CRCM)

INSERM, CBRS, AMU, Institut Paoli-Calmettes

Please join a CV, a motivation letter and the names of two references with email and/or phone number.