<i>NIPBL</i>: a new player in myeloid cell differentiation

Abstract

The nucleophosmin 1 gene (<i>NPM1</i>) is the most frequently mutated gene in acute myeloid leukemia. Notably, <i>NPM1</i> mutations are always accompanied by additional mutations such as those in cohesin genes <i>RAD21</i>, <i>SMC1A</i>, <i>SMC3</i>, and <i>STAG2</i> but not in the cohesin regulator, nipped B-like (<i>NIPBL</i>). In this work, we analyzed a cohort of adult patients with acute myeloid leukemia and <i>NPM1</i> mutation and observed a specific reduction in the expression of <i>NIPBL</i> but not in other cohesin genes. In our zebrafish model, overexpression of the mutated form of <i>NPM1</i> also induced downregulation of <i>nipblb</i>, the zebrafish ortholog of human <i>NIPBL</i> To investigate the hematopoietic phenotype and the interaction between mutated <i>NPM1</i> and <i>nipblb</i>, we generated a zebrafish model with <i>nipblb</i> 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 <i>dkk1b</i> mRNA injection or indomethacin administration. Our results reveal, for the first time, a role for <i>NIPBL</i> during zebrafish hematopoiesis and suggest that an interplay between <i>NIPBL/NPM1</i> may regulate myeloid differentiation in zebrafish and humans through the canonical Wnt pathway and that dysregulation of these interactions may drive leukemic transformation.