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

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

  • Cells. 2021 Jan 19;10(1):192. doi: 10.3390/cells10010192.
Siska Van Belle 1 Sara El Ashkar 1 Kateřina Čermáková 2 Filip Matthijssens 3 4 Steven Goossens 4 5 Alessandro Canella 1 Courtney H Hodges 6 Frauke Christ 1 Jan De Rijck 1 Pieter Van Vlierberghe 3 4 Václav Veverka 2 7 Zeger Debyser 1
Affiliations

Affiliations

  • 1 Laboratory for Molecular Virology and Gene Therapy, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, 3000 Leuven, Flanders, Belgium.
  • 2 Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, Flemingovo nam. 2, 166 10 Prague 6, 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.
Abstract

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.

Keywords

animal model; cell culture; cell proliferation; hematopoietic stem cell; leukemia; molecular cell biology; nuclear magnetic resonance (NMR); protein complex; protein-protein interaction.

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