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Unlike its Paralog LEDGF/p75, HRP-2 Is Dispensable for MLL-R Leukemogenesis but Important for Leukemic Cell Survival
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SYSNO ASEP 0539544 Document Type J - Journal Article R&D Document Type Journal Article Subsidiary J Článek ve WOS Title Unlike its Paralog LEDGF/p75, HRP-2 Is Dispensable for MLL-R Leukemogenesis but Important for Leukemic Cell Survival Author(s) Van Belle, S. (BE)
El Ashkar, S. (BE)
Čermáková, Kateřina (UOCHB-X) ORCID
Matthijssens, F. (BE)
Goossens, S. (BE)
Canella, A. (BE)
Hodges, C. H. (US)
Christ, F. (BE)
De Rijck, J. (BE)
Van Vlierberghe, P. (BE)
Veverka, Václav (UOCHB-X) RID, ORCID
Debyser, Z. (BE)Article number 192 Source Title Cells. - : MDPI
Roč. 10, č. 1 (2021)Number of pages 18 s. Language eng - English Country CH - Switzerland Keywords leukemia ; molecular cell biology ; protein complex ; protein-protein interaction ; nuclear magnetic resonance (NMR) ; animal model ; cell culture ; hematopoietic stem cell ; cell proliferation Subject RIV CE - Biochemistry OECD category Biochemistry and molecular biology R&D Projects GA16-06357S GA ČR - Czech Science Foundation (CSF) LO1304 GA MŠMT - Ministry of Education, Youth and Sports (MEYS) EF16_019/0000729 GA MŠMT - Ministry of Education, Youth and Sports (MEYS) Method of publishing Open access Institutional support UOCHB-X - RVO:61388963 UT WOS 000609981300001 EID SCOPUS 85100326513 DOI 10.3390/cells10010192 Annotation 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. Workplace Institute of Organic Chemistry and Biochemistry Contact asep@uochb.cas.cz ; Kateřina Šperková, Tel.: 232 002 584 ; Jana Procházková, Tel.: 220 183 418 Year of Publishing 2022 Electronic address https://doi.org/10.3390/cells10010192
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