ZFIN ID: ZDB-PUB-100309-12
Expression of the cytoplasmic NPM1 mutant (NPMc+) causes the expansion of hematopoietic cells in zebrafish
Bolli, N., Payne, E.M., Grabher, C., Lee, J.S., Johnston, A.B., Falini, B., Kanki, J.P., and Look, A.T.
Date: 2010
Source: Blood   115(16): 3329-3340 (Journal)
Registered Authors: Grabher, Clemens, Kanki, John, Lee, Jeong-Soo, Look, A. Thomas
Keywords: none
MeSH Terms:
  • Animals
  • Apoptosis/genetics
  • Base Sequence
  • Blotting, Western
  • Cell Separation
  • Cytoplasm/metabolism
  • Embryo, Nonmammalian
  • Flow Cytometry
  • Fluorescent Antibody Technique
  • Hematopoiesis/genetics*
  • Hematopoietic Stem Cells/physiology
  • Humans
  • Immunoprecipitation
  • Leukemia, Myeloid, Acute/genetics*
  • Leukemia, Myeloid, Acute/metabolism
  • Molecular Sequence Data
  • Mutation
  • Myeloid Cells/physiology*
  • Nuclear Proteins/genetics*
  • Nuclear Proteins/metabolism
  • Reverse Transcriptase Polymerase Chain Reaction
  • Sequence Homology, Nucleic Acid
  • Zebrafish
PubMed: 20197555 Full text @ Blood
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 two genes orthologous to human NPM1, referred to as npm1a and npm1b. Both genes are ubiquitously expressed and their knock-down 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 human AML, and both interact with endogenous zebrafish Npm1a and Npm1b. Forced NPMc+ expression in zebrafish causes an increase in pu.1-positive primitive early myeloid cells. A more marked perturbation of myelopoiesis occurs in p53(m/m) embryos expressing NPMC+, where mpx-positive and csf1r-positive cell numbers are also expanded. Importantly, NPMc+ expression results in increased numbers of definitive hematopoietic cells, including erythro-myeloid progenitors in the posterior blood island and c-myb/cd41-positive 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.