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

0539544 - ÚOCHB 2022 RIV CH eng J - Journal Article
Van Belle, S. - El Ashkar, S. - Čermáková, Kateřina - Matthijssens, F. - Goossens, S. - Canella, A. - Hodges, C. H. - Christ, F. - De Rijck, J. - Van Vlierberghe, P. - Veverka, Václav - Debyser, Z.
Unlike its Paralog LEDGF/p75, HRP-2 Is Dispensable for MLL-R Leukemogenesis but Important for Leukemic Cell Survival.
Cells. Roč. 10, č. 1 (2021), č. článku 192. E-ISSN 2073-4409
R&D Projects: GA ČR(CZ) GA16-06357S; GA MŠMT(CZ) LO1304; GA MŠMT(CZ) EF16_019/0000729
Institutional support: RVO:61388963
Keywords : leukemia * molecular cell biology * protein complex * protein-protein interaction * nuclear magnetic resonance (NMR) * animal model * cell culture * hematopoietic stem cell * cell proliferation
OECD category: Biochemistry and molecular biology
Impact factor: 7.666, year: 2021
Method of publishing: Open access
https://doi.org/10.3390/cells10010192

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 MLL-rearranged (MLL-r) leukemia but dispensable for hematopoiesis. Sequel to these findings, we investigated the role of HRP-2 in hematopoiesis and MLL-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 MLL-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 MLL-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.
Permanent Link: http://hdl.handle.net/11104/0317595