Unlike Its Paralog LEDGF/p75, HRP-2 Is Dispensable for MLL-R Leukemogenesis but Important for Leukemic Cell Survival

• Main Authors: Siska Van Belle, Sara El Ashkar, Kateřina Čermáková, Filip Matthijssens, Steven Goossens, Alessandro Canella, Courtney H. Hodges, Frauke Christ, Jan De Rijck, Pieter Van Vlierberghe, Václav Veverka, Zeger Debyser
• Format: Article
• Language: English
• Published: MDPI AG 2021-01-01
• Series: Cells
• Subjects: leukemia; molecular cell biology; protein complex; protein-protein interaction; nuclear magnetic resonance (NMR); animal model
• Online Access: https://www.mdpi.com/2073-4409/10/1/192

HDGF-related protein 2 (HRP-2) is a member of the Hepatoma-Derived Growth Factor-related protein family that harbors the structured PWWP and Integrase Binding Domain, known to associate with methylated histone tails or cellular and viral proteins, respectively. Interestingly, HRP-2 is a paralog of Lens Epithelium Derived Growth Factor p75 (LEDGF/p75), which is essential for <i>MLL</i>-rearranged (<i>MLL</i>-r) leukemia but dispensable for hematopoiesis. Sequel to these findings, we investigated the role of HRP-2 in hematopoiesis and <i>MLL</i>-r leukemia. Protein interactions were investigated by co-immunoprecipitation and validated using recombinant proteins in NMR. A systemic knockout mouse model was used to study normal hematopoiesis and MLL-ENL transformation upon the different HRP-2 genotypes. The role of HRP-2 in <i>MLL</i>-r and other leukemic, human cell lines was evaluated by lentiviral-mediated miRNA targeting HRP-2. We demonstrate that MLL and HRP-2 interact through a conserved interface, although this interaction proved less dependent on menin than the MLL-LEDGF/p75 interaction. The systemic HRP-2 knockout mice only revealed an increase in neutrophils in the peripheral blood, whereas the depletion of HRP-2 in leukemic cell lines and transformed primary murine cells resulted in reduced colony formation independently of <i>MLL</i>-rearrangements. In contrast, primary murine HRP-2 knockout cells were efficiently transformed by the MLL-ENL fusion, indicating that HRP-2, unlike LEDGF/p75, is dispensable for the transformation of MLL-ENL leukemogenesis but important for leukemic cell survival.