Expression of the cytoplasmic NPM1 mutant (NPMc+) causes the expansion of hematopoietic cells in zebrafish

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 human AML, and both interact with endogenous zebrafish Npm1a and Npm1b.

Role of Nucleophosmin Gene Mutation in Leukemogenesis of Acute Myeloid Leukemia

“…These findings are supported by the findings of others who found that mNPM promotes proliferation of myeloid cells in zebra fish embryo and in mice [11,12].…”

Mutations in the Nucleolar Phosphoprotein, Nucleophosmin, Promote the Expression of the Oncogenic Transcription Factor MEF/ELF4 in Leukemia Cells and Potentiates Transformation

“…In zebrafish, forced expression of mutant NPM1 causes an increase in PU.1-positive primitive early myeloid cells (32). Furthermore, in a transgenic mouse expressing the human NPM1 mutant, although spontaneous AML was not found, myeloproliferation occurred in the bone marrow and spleen (33).…”

Nucleophosmin and its complex network: a possible therapeutic target in hematological diseases

“…However, these data demonstrated for the first time that mutant NPM can increase the proliferative potential of myeloid cells. This aspect was confirmed also in the zebrafish model system, in which expression of NPMc þ causes an embryonic expansion of primitive myeloid and definitive hematopoietic cells (Bolli et al, 2010). Although these models provide evidence concerning the capability of NPMc þ to perturb normal hematopoiesis, they still do not provide a definitive NPMc þ dependent AML model system.…”