NIPBL a new player with NPMc+ in the onset of acute myeloid leukemia

Cohesins form a multimeric protein complex (SMC1A, SMC3, RAD21, STAG and additional proteins NIPBL, MAU2, ESCO1, HDAC8) involved in the cohesion of sister chromatids, post-replicative DNA repair and transcriptional regulation. Recently, recurrent somatic mutations and deletions of cohesins have been reported in the 10% of the patients with Acute Myeloid Leukemia (AML) or other myeloid neoplasms. Frequently, mutations in cohesin genes co-occurred with the known AML-associated gene nucleophosmin (NPM1) that, when mutated, aberrantly relocates to the cytoplasm (NPMc+). Forced NPMc+ expression in zebrafish embryos causes an expansion of hematopoietic stem cells (HSCs) according with AML patient features. In our cohort of adult AML patients, we observed a specific and significative reduction of the NIPBL expression in NPMc+ patients. We generated a zebrafish model of nipblb haploinsufficiency to investigate the hematopoietic phenotype and the interactions between NPMc+ and nipblb. In nipblb-loss-of-function zebrafish embryos, we observed an increase in myeloid progenitors, a phenotype resembling the NPMc+ zebrafish model. Therefore, we characterize the functional interaction between NPMc+ and NIPBL in the onset of the aberrant hematopoietic phenotype in zebrafish and showed the involvement of the canonical Wnt pathway in this process. We demonstrate for the first time a role for NIPBL during zebrafish hematopoiesis and that its decreased expression, due to NPM1 mutations, might play a role in leukemia onset. Funding grant: My First AIRC grant (MFAG) 18714