Biochim Biophys Acta Proteins Proteom 2019 Jun 30;1867(6):637-644. Epub 2019 Jan 30.
Department of Pharmacy, University of Naples "Federico II", Italy. Electronic address:
Acute myeloid leukemia (AML) is a clinically and a molecularly heterogeneous disease characterized by the accumulation of undifferentiated and uncontrolled proliferation of hematopoietic progenitor cells. The sub-group named "AML with gene mutations" includes mutations in nucleophosmin (NPM1) assumed as a distinct leukemic entity. NPM1 is an abundant multifunctional protein belonging to the nucleoplasmin family of nuclear chaperones. AML mutated protein is translocated into the cytoplasm (NPM1c+) retaining all functional domains except the loss of a unique NoLs (nucleolar localization signal) at the C-term domain (CTD) and the subsequent disruption of a three helix bundle as tertiary structure. The oligomeric state of NPM1 is of outmost importance for its biological roles and our previous studies linked an aggregation propensity of distinct regions of CTD to leukomogenic potentials of AML mutations. Here we investigated a polypeptide spanning the third and second helices of the bundle of type A mutated CTD. By a combination of several techniques, we ascertained the amyloid character of the aggregates and of fibrils resulting from a self-recognition mechanism. Further amyloid assemblies resulted cytoxic in MTT assay strengthening a new idea of a therapeutic strategy in AML consisting in the self-degradation of mutated NPM1.
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