This project aims to capture the heterogeneity of AML MRD, and identify characteristics of MRD during treatment. The researcher will work in close collaboration with a wet-lab technician to deconstruct MRD-specific features using integrative analysis of scRNA- and single cell assay for transposase-accessible chromatin (scATAC)-sequencing, in combination with single cell protein profiling.

The leukemic (stem cell-like) phenotype of the cells, microenvironment components, and immune cells will be identified by highly multiplexed protein quantification using TotalSeq antibodies. The researcher will make use of AML (poor risk) patient samples at diagnosis, MRD and relapse and AML patient cells purified from an AML patient derived xenograft (PDX) mouse model treated with chemotherapy or venetoclax-based therapy. Selected genes (e.g. related to senescence and cytokine signaling) from the single cell data and previously identified, will be tested for their expression in AML and ALL patient samples and for their functionality as MRD biomarkers and therapy targets. Next, the researcher will in close collaboration with DC5 test the identified genes for their efficiency to function as targets for anti-MRD therapeutics, using small in vivo CRISPR knock-out screens.

Based on results of the CRISPR-Cas9 screening, therapy strategies will be designed and tested, using ex vivo primary AML (stem/progenitor) assays, AML PDX mouse models and “organ on chip” MRD models. 

Host:

Amsterdam AMC, Amsterdam, The Netherlands

Supervisor:

Dr. Linda Smit 

Duration:

48 months, starting 1-5-2025

Profile docatoral candidate:

Master’s degree in Bioinformatics, Computational Biology, Biomedical sciences or a related field. Experience with cancer biology, transcriptomics or epigenetics and/or experience with data analysis (e.g., single cell ATAC-Seq or RNA-Seq).  

In addition:

The researcher will have an intern at VIB-KU Leuven Center for Cancer Biology (4 months, Belgium, supervisor Jan Cools) to analyze scRNA sequencing data and to set up in vivo CRISPR-Cas9 screening, and an intern at Ospedale San Raffaele SRL (3 months, Italy, supervisor Raffaella DiMicco) to study therapy-induced senescence-associated factors as anti-MRD therapy targets.