Expression of the cytoplasmic NPM1 mutant (NPMc+) causes the expansion of hematopoietic cells in zebrafish
Articolo
Data di Pubblicazione:
2010
Citazione:
Expression of the cytoplasmic NPM1 mutant (NPMc+) causes the expansion of hematopoietic cells in zebrafish / N. Bolli, E.M. Payne, C. Grabher, J. Lee, A.B. Johnston, B. Falini, J.P. Kanki, A..T. Look. - In: BLOOD. - ISSN 0006-4971. - 115:16(2010), pp. 3329-3340. [10.1182/blood-2009-02-207225]
Abstract:
Mutations in the human nucleophosmin (NPM1) gene are the most frequent genetic alteration in adult acute myeloid leukemias (AMLs) and result in aberrant cytoplasmic translocation of this nucleolar phosphoprotein (NPMc+). However, underlying mechanisms leading to leukemogenesis remain unknown. To address this issue, we took advantage of the zebrafish model organism, which expresses 2 genes orthologous to human NPM1, referred to as npm1a and npm1b. Both genes are ubiquitously expressed, and their knockdown produces a reduction in myeloid cell numbers that is specifically rescued by NPM1 expression. In zebrafish, wild-type human NPM1 is nucleolar while NPMc+ is cytoplasmic, as in humanAML, and both interact with endogenous zebrafish Npm1a and Npm1b. Forced NPMc+ expression in zebrafish causes an increase in pu.1+ primitive early myeloid cells.Amore marked perturbation of myelopoiesis occurs in p53 m/m embryos expressing NPMc+, where mpx+ and csf1r + cell numbers are also expanded. Importantly, NPMc+ expression results in increased numbers of definitive hematopoietic cells, including erythromyeloid progenitors in the posterior blood island and c-myb/cd41 + cells in the ventral wall of the aorta. These results are likely to be relevant to human NPMc+ AML, where the observed NPMc+ multilineage expression pattern implies transformation of a multipotent stem or progenitor cell.
Tipologia IRIS:
01 - Articolo su periodico
Keywords:
hematology; biochemistry; cell biology; immunology
Elenco autori:
N. Bolli, E.M. Payne, C. Grabher, J. Lee, A.B. Johnston, B. Falini, J.P. Kanki, A..T. Look
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