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NPM1 protein (Nucleophosmin 1) is involved in several cellular processes including centrosome proliferation, chaperone role (stabilization of misfolded proteins), and cell proliferation. The produced phosphoprotein shuttles between the nucleus, nucleus and cytoplasm in the process of chaperone ribosomal proteins and histones from the nucleus nucleus to the cytoplasm.
This protein also sequesters the tumor suppressor ARF in the nucleus and protects it from degradation until it is needed. There are three main types of NPM1 transcripts, the longest of which (i.e., version 1, NPM1 ) contains 11 coding exon fragments and produces a protein of 294 amino acids. Mutation in this gene is associated with acute myeloid leukemia (AML).
AML with mutated NPM1 is a provisional item in the WHO classification of AML and is recommended for testing in patients with cytogenetically normal AML (CN-AML). FLT3 mutations should be evaluated concurrently because they have prognostic implications. Most NPM1 mutations in AML are confined to exon-12 mutations, most commonly W288fs (the most common NPM1 mutation in AML includes [(75% to 80% type A), (10% type B) and 5% type (D)]), which It leads to cytoplasmic sequestration of the protein. NPM1 exon 12 mutation in the absence of FLT3-ITD (one of the most common FLT3 mutations in AML) is associated with good prognostic outcomes.
Mice expressing the Npm1-W288fs mutation develop myeloproliferative neoplasms but no overt leukemia, suggesting that additional mutations may be required to promote leukemia development.
Diseases associated with NPM1 include both solid tumors and blood malignancies such as acute myeloid leukemia with features associated with myelodysplasia and leukemia. While NPM1 protein overexpression has been identified in several solid tumors, hematologic malignancies are variably associated with NPM1 deletions, translocations, and somatic mutations, the latter two with aberrant cytoplasmic translocation in normal NPM1 and/or mutant variants are unified.
Approximately 30% of acute myeloid leukemias and 60% of cases without karyotypic abnormalities (normal karyotype ([NK]-AML) harbor pathogenic somatic mutations at the C-terminal end of NPM1, resulting in a mutated protein product (NPM1c).
NPM1 mutants have long been thought to underlie the pathogenesis of AML. Clinically, AML with mutated NPM1, usually in the absence of other high-risk features such as shared mutations in genes including DNA methyltransferase 3A (DNMT3A) and/or duplications of FMS-like internal tyrosine kinase 3 tandem repeats (FLT3-ITDs), results It is desirable. However, some recent studies have shown that adverse risk is specifically associated with the triple mutation pattern, for example, mutations that are often encountered in NPM1 and DNMT3A alone.
The diagnosis of NPM1-mutated AML, by definition, requires the detection of a pathogenic somatic mutation in a patient who otherwise meets conventional criteria for the diagnosis of AML (ie, >20% blasts in peripheral blood or bone marrow).However , there are many clinicopathologic features characteristic of this leukemia subtype that can help in making a differential diagnosis before the required molecular data are generated: frequent association with monocyte or myelomonocytic cytologic features and phenotype, presence of “cup-like” blasts, absence of CD34 expression, and /or human leukocyte antigen (HLA)-DR and absence of complex cytogenetic lesions.
NPM1 mutations in chronic myeloid proliferations, such as myelodysplastic syndromes and overlapping myelodysplastic/myeloproliferative states, are rare (diagnosed in only 1-5% of cases), although rare, evaluation of such cases can be more complicated because NPM1 mutations can be associated with Multilineage dysplasia. NPM1 mutations are always heterozygous, and complete loss of NPM1wt (wild type) is embryonic lethal, meaning that 1 copy of NPM1wt is essential for cell survival. Npm1 heterozygous knockout mice develop a myelodysplastic-like disorder due to uncontrolled centrosome duplication and aneuploidy. NPM1wt has been shown to be an insufficient tumor suppressor. However, downregulation of NPM1wt in NPM1-mutant AML cells is unlikely to drive leukemia through this mechanism. Indeed, NPM1 mutant AML closely correlates with normal karyotype, as both NPM1wt and NPM1 mutations can properly regulate centrosome duplication.
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