EVI2B is a C/EBP alpha target gene required for granulocytic differentiation and functionality of hematopoietic progenitors

0483248 - ÚMG 2018 RIV GB eng J - Journal Article
Zjablovskaja, Polina - Kardošová, Miroslava - Daněk, Petr - Angelisová, Pavla - Benoukraf, T. - Wurm, A.A. - Kalina, T. - Sian, S. - Balaštík, Martin - Delwel, R. - Brdička, Tomáš - Tenen, D.G. - Malissen, B. - Behre, G. - Fiore, F. - Hořejší, Václav - Alberich-Jorda, Meritxell
EVI2B is a C/EBP alpha target gene required for granulocytic differentiation and functionality of hematopoietic progenitors.
Cell Death and Differentiation. Roč. 24, č. 4 (2017), s. 705-716. ISSN 1350-9047. E-ISSN 1476-5403
R&D Projects: GA ČR(CZ) GAP303/12/0855; GA MŠMT(CZ) LM2015040; GA MŠMT ED2.1.00/19.0395; GA MŠMT(CZ) LQ1604
Institutional support: RVO:68378050 ; RVO:67985823
Keywords : acute myeloid-leukemia * binding protein-alpha * cebpa mutations * expression * induction * phosphorylation * granulopoiesis * cells * block
OECD category: Cell biology; Biochemistry and molecular biology (FGU-C)
Impact factor: 8.000, year: 2017

Development of hematopoietic populations through the process of differentiation is critical for proper hematopoiesis. The transcription factor CCAAT/enhancer binding protein alpha (C/EBP alpha) is a master regulator of myeloid differentiation, and the identification of C/EBPa target genes is key to understand this process. Here we identified the Ecotropic Viral Integration Site 2B (EVI2B) gene as a direct target of C/EBPa. We showed that the product of the gene, the transmembrane glycoprotein EVI2B (CD361), is abundantly expressed on the surface of primary hematopoietic cells, the highest levels of expression being reached in mature granulocytes. Using shRNA-mediated downregulation of EVI2B in human and murine cell lines and in primary hematopoietic stem and progenitor cells, we demonstrated impaired myeloid lineage development and altered progenitor functions in EVI2B-silenced cells. We showed that the compromised progenitor functionality in EvI2b-depleted cells can be in part explained by deregulation of cell proliferation and apoptosis. In addition, we generated an Evi2b knockout murine model and demonstrated altered properties of hematopoietic progenitors, as well as impaired G-CSF dependent myeloid colony formation in the knockout cells. Remarkably, we found that EVI2B is significantly downregulated in human acute myeloid leukemia samples characterized by defects in CEBPA. Altogether, our data demonstrate that EVI2B is a downstream target of C/EBPa, which regulates myeloid differentiation and functionality of hematopoietic progenitors.
Permanent Link: http://hdl.handle.net/11104/0278912