Role of HRP2 in mixed lineage leukemia compared to its paralog LEDGF/p75
Mixed lineage leukemia-rearranged (MLLr) leukemia is a genetically distinct subtype of leukemia driven by a reciprocal chromosomal translocation or partial tandem duplications of internal coding regions of the MLL gene KMT2A. These rearrangements result in in-frame genes, translated to oncogenic fusion proteins deregulating the MLL target genes (e.g. HoxA family, Meis1, Cdk6), promoting leukemogenesis and tumor progression. To regulate gene expression, unstructured N-terminal motifs found in MLL form a ternary complex with menin and the integrase binding domain (IBD) of the p75 splice variant of Lens Epithelium Derived Growth Factor (LEDGF/p75). Formation of the ternary complex is crucial for MLL-r leukemogenesis. Hepatoma derived growth factor related protein 2 (HRP2) is the only human paralog of LEDGF/p75 with identical functional domains. We investigated its role in normal hematopoiesis and leukemia. We demonstrate that adult Hrp2 knockout mice can be distinguished from their wild type littermates by increased neutrophils in the hematopoietic system. Colony formation experiments and Gene Set Enrichment Analysis on lin- HSC hinted towards a stem-like state supported by HRP2. In context of leukemia, we observe a more general role for HRP2 in the survival of leukemic cells independently of MLL. Overall design: mRNA profiling of lineage depleted cells from bone marrow of Hrp2 wildtype and knockout mice (strain C57BL/6N-Hdgfrp2<tm1b (KOMP)Wtsi>/Tcp (Hrp2tm1b)).