New insights into the biology of acute myeloid leukemia with mutated NPM1

• Published in: International journal of hematology 2019-08, Vol.110 (2), p.150-160
• Main Authors: Brunetti, Lorenzo, Gundry, Michael C., Goodell, Margaret A.
• Format: Article
• Language: English
• Subjects: Acute myeloid leukemia; Adults; Animals; Cell Nucleolus - metabolism; Cell Transformation, Neoplastic - genetics; Cytoplasm; Cytoplasm - metabolism; Frameshift Mutation; Gene Expression Regulation, Leukemic; Genes, Homeobox; Genomic Instability; Hematology; HOX gene; Humans; Leukemia; Leukemia, Experimental - genetics; Leukemia, Myeloid, Acute - genetics; Leukemia, Myeloid, Acute - physiopathology; Malignancy; Medicine; Medicine & Public Health; Mice; Mice, Transgenic; Molecular Targeted Therapy; Mutation; Mutation, Missense; Myeloid leukemia; Neoplasm Proteins - antagonists & inhibitors; Neoplasm Proteins - chemistry; Neoplasm Proteins - genetics; Neoplasm Proteins - physiology; Nuclear Proteins - antagonists & inhibitors; Nuclear Proteins - chemistry; Nuclear Proteins - genetics; Nuclear Proteins - physiology; Nuclear transport; Nucleoli; Oncology; Progress in Hematology; Protein Domains; Protein Isoforms - chemistry; Protein Isoforms - physiology; Protein Transport; Proteins; Structure-Activity Relationship
• ISSN: 0925-5710; 1865-3774
• DOI: 10.1007/s12185-018-02578-7

Acute myeloid leukemia (AML), the most common acute leukemia in adults, increases exponentially with age. While a number of recent advances have improved treatment, high cure rates have not yet been achieved. Nucleophosmin ( NPM1 ) is found mutated in nearly one-third of newly diagnosed cases and leads to NPM1 protein that is mislocalized to the cytoplasm instead of the nucleolus. If the mechanistic basis through which this mislocalization leads to malignancy could be revealed, this AML subtype may be targetable with new drugs. Here, we review the structure and functions of the normal and mutant forms of nucleophosmin. We discuss several recent studies that have shed light on the pathophysiology of NPM1 mutations. We discuss the importance of HOX gene misregulation in NPM1 -mutated leukemias, as well as evidence for the reliance of mutated NPM1 on its continued nuclear export. Together, these aspects, as well as new tools to manipulate and study NPM1, open the door to new therapeutic strategies that may ultimately improve treatment of this common subtype of AML.