Unlike Its Paralog LEDGF/p75, HRP-2 Is Dispensable for MLL-R Leukemogenesis but Important for Leukemic Cell Survival
Jazyk angličtina Země Švýcarsko Médium electronic
Typ dokumentu časopisecké články, Research Support, N.I.H., Extramural, práce podpořená grantem
Grantová podpora
R00 CA187565
NCI NIH HHS - United States
PubMed
33477970
PubMed Central
PMC7835958
DOI
10.3390/cells10010192
PII: cells10010192
Knihovny.cz E-zdroje
- Klíčová slova
- animal model, cell culture, cell proliferation, hematopoietic stem cell, leukemia, molecular cell biology, nuclear magnetic resonance (NMR), protein complex, protein-protein interaction,
- MeSH
- adaptorové proteiny signální transdukční genetika metabolismus MeSH
- HEK293 buňky MeSH
- histonlysin-N-methyltransferasa genetika metabolismus MeSH
- karcinogeneze genetika metabolismus patologie MeSH
- leukemie genetika metabolismus patologie MeSH
- lidé MeSH
- myši knockoutované MeSH
- myši MeSH
- proteiny buněčného cyklu genetika metabolismus MeSH
- protoonkogenní protein MLL genetika metabolismus MeSH
- transkripční faktory genetika metabolismus MeSH
- viabilita buněk MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Research Support, N.I.H., Extramural MeSH
- Názvy látek
- adaptorové proteiny signální transdukční MeSH
- Hdgfl2 protein, mouse MeSH Prohlížeč
- histonlysin-N-methyltransferasa MeSH
- KMT2A protein, human MeSH Prohlížeč
- Kmt2a protein, mouse MeSH Prohlížeč
- proteiny buněčného cyklu MeSH
- protoonkogenní protein MLL MeSH
- PSIP1 protein, human MeSH Prohlížeč
- transkripční faktory MeSH
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.
Cancer Research Institute Ghent 9000 Ghent Belgium
Department of Biomolecular Medicine Ghent University 9000 Ghent Belgium
Department of Cell Biology Faculty of Science Charles University 128 00 Prague Czech Republic
Department of Diagnostic Sciences Ghent University 9000 Ghent Belgium
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