The "Acute Myeloid Leukemia with gene mutations'' group includes mutations in Nucleophosmin 1(NPM1) that is an abundant multifunctional protein with chaperon functions. This protein also takes part to rRNA maturation in ribosome biogenesis, tumor suppression and nucleolar stress response. Mutations of NPM1 associated to AML present in its C-terminal domain (CTD) unable its correct folding and confer it an aberrant cytoplasmatic localization (NPMc+). AML cells with NPM1 mutations retain a certain amount of wt NPM1 in the nucleolus and since NPM1 acts as a hub protein, the nucleolus of AML cells are more vulnerable with respect to cells expressing only wt NPM1. Thus, interfering with the levels or the oligomerization status of NPM1 may influence its capability to properly build up the nucleolus in AML cells. Our biophysical recent results demonstrated that AML-CTDs contain regions prone to amyloid aggregation and, herein, we present results oriented to exploit this amylodogenesis in a potential therapeutic way. We evaluated the different ability of two small molecules to enhance amyloid aggregation through complementary biophysical approaches as fluorescence and Circular Dichroism spectroscopies, Scanning Electron Microscopy and cell-viability assays, to evaluate the cytoxicity of these molecules in AML cells lines. These findings could pave the way into molecular mechanisms of NPM1c and in novel therapeutic routes toward AML progression.

Small molecules enhancers of amyloid aggregation of C-terminal domain of Nucleophosmin 1 in acute myeloid leukemia

Florio, Daniele;Roviello, Valentina;La Manna, Sara;Maria Malfitano, Anna;Marasco, Daniela
2022

Abstract

The "Acute Myeloid Leukemia with gene mutations'' group includes mutations in Nucleophosmin 1(NPM1) that is an abundant multifunctional protein with chaperon functions. This protein also takes part to rRNA maturation in ribosome biogenesis, tumor suppression and nucleolar stress response. Mutations of NPM1 associated to AML present in its C-terminal domain (CTD) unable its correct folding and confer it an aberrant cytoplasmatic localization (NPMc+). AML cells with NPM1 mutations retain a certain amount of wt NPM1 in the nucleolus and since NPM1 acts as a hub protein, the nucleolus of AML cells are more vulnerable with respect to cells expressing only wt NPM1. Thus, interfering with the levels or the oligomerization status of NPM1 may influence its capability to properly build up the nucleolus in AML cells. Our biophysical recent results demonstrated that AML-CTDs contain regions prone to amyloid aggregation and, herein, we present results oriented to exploit this amylodogenesis in a potential therapeutic way. We evaluated the different ability of two small molecules to enhance amyloid aggregation through complementary biophysical approaches as fluorescence and Circular Dichroism spectroscopies, Scanning Electron Microscopy and cell-viability assays, to evaluate the cytoxicity of these molecules in AML cells lines. These findings could pave the way into molecular mechanisms of NPM1c and in novel therapeutic routes toward AML progression.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11588/899478
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