34 Discovery of NPM1 mutations in AML originated from the simple

34 Discovery of NPM1 mutations in AML originated from the simple observation at the microscope that bone marrow biopsies from about one-third of AML showed ectopic expression of nucleophosmin in the cytoplasm of leukemic cells. 35 This immunohistochemical finding led in turn to sequence the NPM1 gene and to discover mutations occurring at exon-12. 35 Subsequent studies have reported more than 50 different types of NPM1 mutations, 14 including a unique case occurring at exon-11. 36 Notably, all these mutation variants result into common

Selleckchem PD-332991 changes at the C-terminus of the native NPM1 protein, i.e. the disruption of the nucleolar localization signal and the generation of a new additional nuclear export signal motif. [37] and [38] These changes interfere with the normal nucleo-cytoplasmic traffic of the protein, leading to the aberrant

accumulation of nucleophosmin in the cytoplasm of leukemic cells carrying NPM1 mutations. [37] and [38] Cytoplasmic nucleophosmin is easily detectable by immunohistochemistry in routinely fixed paraffin-embedded samples. 39 This technique can be used as surrogate for molecular analysis 39 especially useful for the diagnosis of NPM1-mutated myeloid sarcomas. 40 NPM1 mutations are the most common single gene abnormality so far identified in adult AML, accounting for about 30% of all AML and 50-60% of CN-AML. 41 Their Osimertinib clinical trial frequency (as well as that of FLT3-ITD mutations) seems to decrease with age in adult CN-AML. 42 Several evidences point to NPM1 mutations as a founder genetic alteration in AML 14 ( Table 1). Unlike other mutations, those affecting

the NPM1 gene appear specific for AML, 43 and usually occur in patients with de novo disease. 44NPM1 mutations in AML are highly stable during the course of the disease, being detected at relapse even many years after the initial diagnosis, in patients with more than one relapse and even in relapses that occur in extramedullary sites. 14 Loss of NPM1 mutations has been very rarely reported in NPM1-mutated AML but the nature of these cases remains controversial since no in-depth studies were carried out Arachidonate 15-lipoxygenase to exclude that they represented a secondary, clonally unrelated AML. As expected for a founder genetic lesion, NPM1 mutations are mutually exclusive of other AML recurrent genetic abnormalities, 7 including double CEBPA mutations. 14 In addition, NPM1-mutated AML is associated with a distinct gene expression profile (including down-regulation of CD34 and up-regulation of HOX genes) 45 and a unique microRNA signature (up-regulation of miR-10a and miR-10b). 46NPM1 mutations appear dominant over other secondary AML features, such as chromosomal abnormalities 47 or multilineage dysplasia, 48 that are present in about 15% and 23% of NPM1-mutated cases, respectively.

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