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Open AccessArticle

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

1
Laboratory for Molecular Virology and Gene Therapy, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, 3000 Leuven, Belgium
2
Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, Flemingovo nam. 2, 166 10 Prague, Czech Republic
3
Department of Biomolecular Medicine, Ghent University, 9000 Ghent, Belgium
4
Cancer Research Institute Ghent (CRIG), 9000 Ghent, Belgium
5
Department of Diagnostic Sciences, Ghent University, 9000 Ghent, Belgium
6
Department of Molecular & Cellular Biology, Center for Precision Environmental Health, and Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA
7
Department of Cell Biology, Faculty of Science, Charles University, 128 00 Prague, Czech Republic
*
Author to whom correspondence should be addressed.
These authors contributed equally to the work.
Cells 2021, 10(1), 192; https://doi.org/10.3390/cells10010192
Received: 24 November 2020 / Revised: 11 January 2021 / Accepted: 15 January 2021 / Published: 19 January 2021
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. View Full-Text
Keywords: leukemia; molecular cell biology; protein complex; protein-protein interaction; nuclear magnetic resonance (NMR); animal model; cell culture; hematopoietic stem cell; cell proliferation leukemia; molecular cell biology; protein complex; protein-protein interaction; nuclear magnetic resonance (NMR); animal model; cell culture; hematopoietic stem cell; cell proliferation
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MDPI and ACS Style

Van Belle, S.; El Ashkar, S.; Čermáková, K.; Matthijssens, F.; Goossens, S.; Canella, A.; Hodges, C.H.; Christ, F.; De Rijck, J.; Van Vlierberghe, P.; Veverka, V.; Debyser, Z. Unlike its Paralog LEDGF/p75, HRP-2 Is Dispensable for MLL-R Leukemogenesis but Important for Leukemic Cell Survival. Cells 2021, 10, 192. https://doi.org/10.3390/cells10010192

AMA Style

Van Belle S, El Ashkar S, Čermáková K, Matthijssens F, Goossens S, Canella A, Hodges CH, Christ F, De Rijck J, Van Vlierberghe P, Veverka V, Debyser Z. Unlike its Paralog LEDGF/p75, HRP-2 Is Dispensable for MLL-R Leukemogenesis but Important for Leukemic Cell Survival. Cells. 2021; 10(1):192. https://doi.org/10.3390/cells10010192

Chicago/Turabian Style

Van Belle, Siska; El Ashkar, Sara; Čermáková, Kateřina; Matthijssens, Filip; Goossens, Steven; Canella, Alessandro; Hodges, Courtney H.; Christ, Frauke; De Rijck, Jan; Van Vlierberghe, Pieter; Veverka, Václav; Debyser, Zeger. 2021. "Unlike its Paralog LEDGF/p75, HRP-2 Is Dispensable for MLL-R Leukemogenesis but Important for Leukemic Cell Survival" Cells 10, no. 1: 192. https://doi.org/10.3390/cells10010192

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