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NIPBL: a new player in myeloid cells differentiation

Haematopoietic stem cell

Haematopoietic stem cell in the caudal tissue of a Tg(CD41:EGFP) transgenic zebrafish embryos.

 

 

NIPBL: a new player in myeloid cells differentiation

NUCLEOPHOSMIN1 (NPM1) is the most frequently mutated gene in acute myeloid leukemia. Notably, NPM1 mutations are always accompanied by additional mutations such as those in cohesion genes RAD21, SMC1A, SMC3, STAG2 but not in the cohesin regulator NIPBL. In this work, we analyze a cohort of adult patients with acute myeloid leukemia and NPM1 mutation and we observe specific reduction in the expression of NIPBL but not in other cohesin genes. In our zebrafish model, the overexpression of the mutated form of NPM1 also induced the down-regulation of nipblb, the zebrafish orthologue of the human NIPBL. To investigate the hematopoietic phenotype and the interaction between mutated NPM1 and nipblb, we generate a zebrafish model with nipblb down-regulation that shows an increased number of myeloid progenitors. This phenotype is due to a hyper activation of the canonical Wnt pathway: the rescue of myeloid cells blocked in an undifferentiated state is possible when the Wnt pathway is inhibited by ddk1b mRNA injection or indomethacin administration. Our results reveal for the first time a role for NIPBL during zebrafish hematopoiesis and suggest that NIPBL/NPM1 interplay may regulate myeloid differentiation in zebrafish and humans through the canonical Wnt pathway and that dysregulation of these interactions may drive to leukemic transformations.

 

Publication:
“NIPBL: a new player in myeloid cell differentiation”. Haematologica. 2019 Jul;104(7):1332-1341. doi: 10.3324/haematol.2018.200899. Epub 2019 Jan 10.

 

Contacts:
Anna Pistocchi anna.pistocchi@unimi.it

 

02 August 2019
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