Proteostasis unbalance of nucleophosmin 1 in Acute Myeloid Leukemia: An aggregomic perspective.

Abstract

The role exerted by the nucleus in the regulation of proteostasis in both health and disease is recognized of outmost importance, even though not fully understood. Many recent investigations are focused on its ability to modulate and coordinate protein quality control machineries in mammalian cells. Nucleophosmin 1 (NPM1) is one of the most abundant nucleolar proteins and its gene is mutated in ~30% of Acute Myeloid Leukemia (AML) patients. Mutations are localized in the C-terminal domain of the protein and cause cytoplasmatically delocalized and possibly aggregated forms of NPM1 (NPM1c+). Therapeutic interventions targeted on NPM1c+ are in demand and, to this end, deeper knowledge of NPM1c+ behavior in the blasts' cytosol is required. Here by means of complementary biophysical techniques we compared the conformational and aggregative behavior of the entire C-terminal domains of NPM1wt and type A NPM1c+ (bearing the most common mutation). Overall data show that only Cterm_mutA is able to form amyloid-like assemblies with fibrillar morphology and that the oligomers are toxic in human neuroblastoma SHSY cells. This study adds a novel piece of knowledge to the comprehension of the molecular roles exerted by cytoplasmatic NPM1c+ and suggests the exploitation of the amyloidogenic propensity of NPM1c+ as a new strategy for targeting AML with NPM1 mutations.

• Authors: Concetta Di Natale, Daniele Florio, Sarah Di Somma, Adele Di Matteo, Luca Federici, Paolo Antonio Netti, Giancarlo Morelli, Anna Maria Malfitano, Daniela Marasco
• Journal: International journal of biological macromolecules (Int J Biol Macromol) Vol. 164 Pg. 3501-3507 (Dec 01 2020) ISSN: 1879-0003 [Electronic] Netherlands
• PMID: 32890557 (Publication Type: Journal Article)
• Copyright: Copyright © 2020 Elsevier B.V. All rights reserved.

Chemical References

• Amyloid
• Amyloidogenic Proteins
• NPM1 protein, human
• Nuclear Proteins
• Nucleophosmin

Topics

• Amino Acid Sequence
• Amyloid (metabolism)
• Amyloidogenic Proteins (metabolism)
• Humans
• Leukemia, Myeloid, Acute (etiology, metabolism)
• Mutation
• Nuclear Proteins (genetics, metabolism)
• Nucleophosmin
• Protein Aggregation, Pathological
• Proteomics (methods)
• Proteostasis