NIPBL: a new player in myeloid cell differentiation
| Autor: | Mara Mazzola, Gianluca Deflorian, Alex Pezzotta, Laura Ferrari, Grazia Fazio, Erica Bresciani, Claudia Saitta, Luca Ferrari, Monica Fumagalli, Matteo Parma, Federica Marasca, Beatrice Bodega, Paola Riva, Franco Cotelli, Andrea Biondi, Anna Marozzi, Gianni Cazzaniga, Anna Pistocchi |
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| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: | |
| Zdroj: | Haematologica, Vol 104, Iss 7 (2019) |
| Druh dokumentu: | article |
| ISSN: | 0390-6078 1592-8721 51750740 |
| DOI: | 10.3324/haematol.2018.200899 |
| Popis: | The nucleophosmin 1 gene (NPM1) is the most frequently mutated gene in acute myeloid leukemia. Notably, NPM1 mutations are always accompanied by additional mutations such as those in cohesin genes RAD21, SMC1A, SMC3, and STAG2 but not in the cohesin regulator, nipped B-like (NIPBL). In this work, we analyzed a cohort of adult patients with acute myeloid leukemia and NPM1 mutation and observed a specific reduction in the expression of NIPBL but not in other cohesin genes. In our zebrafish model, overexpression of the mutated form of NPM1 also induced downregulation of nipblb, the zebrafish ortholog of human NIPBL. To investigate the hematopoietic phenotype and the interaction between mutated NPM1 and nipblb, we generated a zebrafish model with nipblb downregulation which showed an increased number of myeloid progenitors. This phenotype was due to hyper-activation of the canonical Wnt pathway: myeloid cells blocked in an undifferentiated state could be rescued when the Wnt pathway was inhibited by dkk1b mRNA injection or indomethacin administration. Our results reveal, for the first time, a role for NIPBL during zebrafish hematopoiesis and suggest that an interplay between NIPBL/NPM1 may regulate myeloid differentiation in zebrafish and humans through the canonical Wnt pathway and that dysregulation of these interactions may drive leukemic transformation. |
| Databáze: | Directory of Open Access Journals |
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