期刊
BLOOD REVIEWS
卷 32, 期 3, 页码 167-183出版社
CHURCHILL LIVINGSTONE
DOI: 10.1016/j.blre.2017.11.001
关键词
Acute myeloid leukemia (AML); differentiation; NPM1c+; gain-of-function, apoptosis; nuclear export signal (NES)
类别
资金
- University of Kansas Cancer Center [NCI-P30CA168524]
- Sosland Family Foundation
- University of Kansas Medical Center Basic Research Development Award
Nucleophosmin 1 (NPM1) is a nucleolar phosphoprotein that performs diverse biological functions including molecular chaperoning, ribosome biogenesis, DNA repair, and genome stability. Acute myeloid leukemia (AML) is a heterogeneous disease, more than half of the AML cases exhibit normal karyotype (NK). Approximately 50-60 percent of patients with NK-AML carry NPM1 mutations which are characterized by cytoplasmic dislocation of the NPM1 protein. In AML, mutant NPM1 (NPM1c +) acts in a dominant negative fashion and also blocks the differentiation of myeloid cells through gain-of-function for the AML phenotype. Currently, there is limited knowledge on the gain-of-function mechanism of mutant NPM1. Here, we review the known mechanisms of mutant NPM1 in the pathogenesis of AML. We describe genetic abnormalities, the clinical significance of exon-12 mutations in the NPM1 gene, and chromosomal translocations including the recently discovered NPM1-TYK2, and NPM1-HAUS1. Also, we outline the possible therapeutic interventions for the treatment of AML by targeting NPM1. Overall, the review will summarize present knowledge on mutant NPM1 origin, pathogenesis, and therapy in AML.
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