When the good go bad: Mutant NPM1 in acute myeloid leukemia

Kunchala, Preethi; Kuravi, Sudhakiranmayi; Jensen, Roy A.; McGuirk, Joseph P.; Balusu, Ramesh

doi:10.1016/j.blre.2017.11.001

Cited by 72 publications

(58 citation statements)

References 193 publications

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“…As a result, the nucleolar localization signal is lost and the protein relocalizes within the cytoplasm [101]. Furthermore, NPM1 mutants (NPM1c) acquire the ability to impound the wild-type form, preventing the NPM1 wild-type tumor suppressor functions [108]. Mouse models of mutated NPM1 (NPM1c) support the importance of NPM1c as a cooperative event in leukemogenesis, but not to initiate leukemia [109].…”

Section: Npm1 Mutationsmentioning

confidence: 99%

Landscape of Tumor Suppressor Mutations in Acute Myeloid Leukemia

Panuzzo

Signorino

Calabrese

et al. 2020

JCM

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Acute myeloid leukemia is mainly characterized by a complex and dynamic genomic instability. Next-generation sequencing has significantly improved the ability of diagnostic research to molecularly characterize and stratify patients. This detailed outcome allowed the discovery of new therapeutic targets and predictive biomarkers, which led to develop novel compounds (e.g., IDH 1 and 2 inhibitors), nowadays commonly used for the treatment of adult relapsed or refractory AML. In this review we summarize the most relevant mutations affecting tumor suppressor genes that contribute to the onset and progression of AML pathology. Epigenetic modifications (TET2, IDH1 and IDH2, DNMT3A, ASXL1, WT1, EZH2), DNA repair dysregulation (TP53, NPM1), cell cycle inhibition and deficiency in differentiation (NPM1, CEBPA, TP53 and GATA2) as a consequence of somatic mutations come out as key elements in acute myeloid leukemia and may contribute to relapse and resistance to therapies. Moreover, spliceosomal machinery mutations identified in the last years, even if in a small cohort of acute myeloid leukemia patients, suggested a new opportunity to exploit therapeutically. Targeting these cellular markers will be the main challenge in the near future in an attempt to eradicate leukemia stem cells.

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Section: Npm1 Mutationsmentioning

confidence: 99%

Landscape of Tumor Suppressor Mutations in Acute Myeloid Leukemia

Panuzzo

Signorino

Calabrese

et al. 2020

JCM

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“…The prognostic effect of NPM1 mutation in de novo AML may be influenced by the mutated allele burden (16). Other studies reported also that co-occurrance of NPM1 mutations with other common gene mutations in AML patients is associated with a poor prognosis (17). NPM1 mutations are considered to be mutually exclusive with other genomic rearrangements and/or chromosomal aneuploidy in AML patients.…”

Section: Npm1 Gene Mutationmentioning

confidence: 99%

The Value of FLT3, NPM1 and DNMT3A Gene Mutation Analysis in Acute Myeloid Leukemia Diagnosis

Bănescu

Skrypnyk

2019

Revista Romana De Medicina De Laborator

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“…Furthermore, mutated proteins present peculiar features in their cellular localization, also due to their hetero-oligomerization with wt form: the ability of NPM1 to form oligomers is never disrupted by any type of C-terminal mutation but seems to be generally lowered, irrespective of the mutation type [24]. The combination of haploinsufficiency and the gain-of-function of NPMc+ contribute to the pathogenesis of AML [25,26]. Our recent data showed, unexpectedly, that several protein regions of the CTD form amyloid-like assemblies with fibrillar morphology, toxic in cell viability assays [10,27,28] and able to differently interact with model cellular membranes [29].…”

Section: Introductionmentioning

confidence: 99%

The acute myeloid leukemia‐associated Nucleophosmin 1 gene mutations dictate amyloidogenicity of the C‐terminal domain

et al. 2019

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Nucleophosmin 1 (NPM1) is a nucleus‐cytoplasm shuttling protein ubiquitously expressed and highly conserved. It is involved in many cellular processes and its gene is mutated in ~ 50–60% of Acute Myeloid Leukemia (AML) patients. These mutations cause its cytoplasmic mislocation and accumulation (referred to as NPM1c+) and open the door to rational targeted therapy for AML diseases with mutated NPM1. Currently, there is limited knowledge on the mechanism of action of NPM1c+ and on structural determinants of the leukemogenic potential of AML mutations. Numerous previous studies outlined an unexpected amyloid‐like aggregation tendency of several regions located in the C‐terminal domain that, in wild‐type form, fold as a three‐helical‐bundle. Here, using a combination of different techniques including Thioflavin T fluorescence, congo red absorbance, CD spectroscopy, Scanning Electron Microscopy (SEM) and wide‐angle X‐ray scattering on a series of peptides bearing mutations, we evidence that the amyloidogenicity of NPM1 mutants is directly linked to AML. Noticeably, AML point mutations strongly affect the amyloid cytotoxic effects in neuroblastoma cells and the morphologies of deriving fibrils. This study paves the way to deepen our understanding of AML‐associated NPM1 mutants, and could help to break new ground for the identification of novel drugs targeting NPM1c+ for treatment of AML.

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When the good go bad: Mutant NPM1 in acute myeloid leukemia

Cited by 72 publications

References 193 publications

Landscape of Tumor Suppressor Mutations in Acute Myeloid Leukemia

Landscape of Tumor Suppressor Mutations in Acute Myeloid Leukemia

The Value of FLT3, NPM1 and DNMT3A Gene Mutation Analysis in Acute Myeloid Leukemia Diagnosis

The acute myeloid leukemia‐associated Nucleophosmin 1 gene mutations dictate amyloidogenicity of the C‐terminal domain

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