Adhesion GPCR signaling in hematopoietic stem and progenitor cells

• Applicant: Dr. Caroline Pabst
• Subject Area: Pharmacology
• Term: from 2017 to 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 246212759

Knowledge about the differences and similarities between normal and malignant hematopoietic stem and progenitor cells (HSPCs) is crucial for the development of more efficacious anti-leukemic therapeutic approaches. We recently identified the adhesion G protein-coupled receptor ADGRG1/GPR56 as a novel marker discriminating the leukemia stem cell (LSC) compartment from non-LSC blasts in acute myeloid leukemia. We found evidence that besides from being a marker for leukemic stem cells GPR56 might also play a crucial role for the in vitro and in vivo function of normal HSPCs, as GPR56 knockdown severely reduced colony formation and engraftment capacity of CD34+ cord blood cells.Analysis of RNA Sequencing data of multiple hematopoietic populations sorted from normal bone marrow revealed that several other adhesion GPCRs show distinct expression patterns in immature and differentiated bone marrow cell populations similar to GPR56. We therefore hypothesize that adhesion GPCR signaling via GPR56 and other aGPCRs is tightly regulated by intrinsic and extrinsic factors controlling self-renewal and differentiation. To approach this hypothesis we will dissect GPR56 signaling in the hematopoietic system using a Gpr56 inducible knockout model, and by performing structure-function analyses in primary human HSPCs. In an independent approach, we will identify whether other aGPCRs with similar expression patterns in human HSPCs compared to GPR56 have non-redundant functional roles in the hematopoietic system. Knowledge gained from these experiments will lead to a better understanding of adhesion GPCR signaling in the hematopoietic system and will elucidate whether aGPCRs might represent suitable therapeutic targets.

• DFG Programme: Research Units
• Subproject of: FOR 2149: Elucidation of Adhesion-GPCR Signalling