Genetic variation influencing blood cancer risk and blood stem cell activity

We focus on how inborn genetic variation influences blood cell formation and blood cancer risk.In Project A, we will explore genetic predisposition to multiple myeloma (MM). Since 2010, we have led an international network to map the molecular basis of MM predisposition. In genome-wide association studies reaching ~11,000 cases, we have discovered 35 MM risk loci.

Here, we will carry out an expanded association study (n = 22,000) and functional studies to understand the underlying mechanisms.In Project B, we will explore an innovative approach to find drug targets for stem cell mobilization.

Recently, in a genome-wide association study on 13,176 individuals, we discovered 11 loci influencing blood CD34+ cell levels. The most significant gene, PPM1H, encodes a protein phosphatase never linked to stem cell biology before. Downregulation of PPM1H increased blood CD34+ cell levels.

Here, we will search for PPM1H inhibitors and conduct deeper genetic studies on CD34+ cell levels in adults (n = 40,000) and newborns (n = 13,000).Both projects build on extensive preliminary work, unique samples, and advanced genomics and genome editing techniques. They will be, by far, the most extensive studies in their respective areas to date.

They will be carried out by an experienced team and facilitated by long-standing international collaborations. They will lead to a better understanding of blood malignancies and new strategies for stem cell mobilization.