Objective While mutations at protein-coding sequences have been extensively characterized, the functional role of disease-associated non-coding variants remains largely elusive. In fact, germline non-coding variants are often associated with increased risk of childhood cancers. In B-cell derived acute lymphoblastic leukemia (B-ALL), the most common type of cancer in children, non-coding sequence variation at lineage-specific genes, such as IKZF1, GATA3 and CEBPE is associated with disease. Interestingly, the strongest risk factor maps at ARID5B, a DNA-binding protein described to promote the removal of repressive histone marks. Still, the role of ARID5B in leukemia and haematopoiesis remains largely uncharacterized. Thus, we hypothesize that non-coding variants associated with B-ALL affect the activity of distal regulatory elements, modulating the expression of ARID5B and other B-cell lineage-specific genes (objective 1). We further postulate that ARID5B promotes the de-repression of lineage-specific genes (objective 2), playing a crucial role in B-cell development and B-ALL initiation and progression (objective 3). To test these hypotheses, I will develop a novel CRISPR screen approach to dissect ARID5B enhancers at single nucleotide resolution (work package 1). I will use a combination of genomics and transcriptomics methods after acute and prolonged degradation of ARID5B to elucidate the molecular function of ARID5B in B-ALL (work package 2). Finally, I will use mouse models and focus on the physiological relevance of ARID5B in B-cell development and leukemia initiation and progression, in vivo. (work package 3). Together, I will dissect the role of non-coding variants at leukemia-associated loci, characterize the molecular function of ARID5B and elucidate the pathophysiological relevance of ARID5B. Fields of science natural sciencesbiological sciencesbiochemistrybiomoleculesproteinsnatural sciencesbiological sciencesgeneticsmutationnatural sciencesbiological sciencesgeneticsnucleotidesmedical and health sciencesclinical medicineoncologyleukemia Programme(s) HORIZON.1.2 - Marie Skłodowska-Curie Actions (MSCA) Main Programme Topic(s) HORIZON-MSCA-2021-PF-01-01 - MSCA Postdoctoral Fellowships 2021 Call for proposal HORIZON-MSCA-2021-PF-01 See other projects for this call Funding Scheme HORIZON-AG-UN - HORIZON Unit Grant Coordinator ST. ANNA KINDERKREBSFORSCHUNG GMBH Net EU contribution € 183 600,96 Address Zimmermannplatz 10 1090 Wien Austria See on map Region Ostösterreich Wien Wien Activity type Research Organisations Links Contact the organisation Opens in new window Participation in EU R&I programmes Opens in new window HORIZON collaboration network Opens in new window EU contribution No data Partners (1) Sort alphabetically Sort by Net EU contribution Expand all Collapse all CEMM - FORSCHUNGSZENTRUM FUER MOLEKULARE MEDIZIN GMBH Austria Net EU contribution € 0,00 Address Lazarettgasse 14 akh bt 25.3 1090 Wien See on map Region Ostösterreich Wien Wien Activity type Private for-profit entities (excluding Higher or Secondary Education Establishments) Links Contact the organisation Opens in new window Website Opens in new window Participation in EU R&I programmes Opens in new window HORIZON collaboration network Opens in new window Other funding No data
