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Ferrata Storti Foundation
Haematologica 2019 Volume 104(7):1332-1341
NIPBL: a new player in myeloid cell differentiation
Mara Mazzola,1* Gianluca Deflorian,2* Alex Pezzotta,1 Laura Ferrari,2 Grazia Fazio,3 Erica Bresciani,4 Claudia Saitta,3 Luca Ferrari,1 Monica Fumagalli,5 Matteo Parma,5 Federica Marasca,6 Beatrice Bodega,6 Paola Riva,1 Franco Cotelli,7 Andrea Biondi,3 Anna Marozzi,1 Gianni Cazzaniga3 and Anna Pistocchi1
1Dipartimento di Biotecnologie Mediche e Medicina Traslazionale, Università degli Studi di
Milano, LITA, Segrate, Italy; 2Istituto FIRC di Oncologia Molecolare, IFOM, Milano, Italy;
3
Centro Ricerca Tettamanti, Clinica Pediatrica Università di Milano-Bicocca, Centro Maria
Letizia Verga, Monza, Italy; 4Oncogenesis and Development Section, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA; 5Clinica Ematologica e Centro Trapianti di Midollo Osseo, Ospedale San Gerardo, Università di Milano-Bicocca, Monza, Italy; 6Istituto Nazionale di Genetica Molecolare "Romeo ed Enrica Invernizzi" (INGM), Milano, Italy and 7Dipartimento di Bioscienze, Università degli Studi di Milano, Milano, Italy.
Hematopoiesis
* MM and GDF contributed equally to this work
ABSTRACT
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 inter- action 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 dys- regulation of these interactions may drive leukemic transformation.
Introduction
Acute myeloid leukemia (AML) is an aggressive hematologic malignancy of bone marrow characterized by the accumulation of immature myeloid blasts that show defective differentiation and function.1,2 Advances in cancer genomics have shown that relatively few recurrent somatic mutations give rise to human AML, with an average of five mutations in each case of de novo AML.3 These somatic mutations, which collectively determine the malignant phenotype, are serially acquired in clones of self-renewing hematopoietic stem cells (HSC), termed pre-leukemic HSC.4 The genes mutated in HSC that are relevant in the pathogenesis of AML have been divided into nine categories, including transcription-factor fusions, nucleophosmin (NPM1), tumor-suppressor genes, DNA-methylation–related genes, signaling genes, chromatin-modifying genes, myeloid transcription-factor genes, cohesin-complex genes and spliceosome-complex genes.5
NPM1, the most frequently mutated gene in AML, is a phosphoprotein that nor- mally resides in the nucleolus.6,7 More than 50 different reported mutations in human NPM1 result in aberrant cytoplasmic translocation of the protein, named
Correspondence:
ANNA PISTOCCHI
anna.pistocchi@unimi.it
Received: July 5, 2018. Accepted: January 3, 2019. Pre-published: January 10, 2019.
doi:10.3324/haematol.2018.200899
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