NPM1

Overview

NPM1 (Nucleophosmin 1) is a multifunctional nucleocytoplasmic shuttling protein mutated in ~27% of adult AML. NPM1 mutations cause aberrant cytoplasmic dislocation of the protein and are among the most common somatic mutations in AML, defining an intermediate-risk subtype when co-occurring with DNMT3A and FLT3 mutations. NPM1 is already incorporated into major AML classification systems as a biomarker.

Alterations observed in the corpus

  • Mutated in 27% of 200 adult de novo AML cases (TCGA AML cohort); central co-occurring node with DNMT3A (P<6.3×10⁻⁷) and FLT3 (P<1.9×10⁻⁶); concurrent NPM1 + DNMT3A + FLT3 samples clustered together in mRNA, miRNA, and DNA-methylation space, defining a putative novel AML subtype PMID:23634996
  • NPM1 is mutually exclusive of transcription-factor fusions (PML–RARA, MYH11–CBFB, KMT2A fusions) and of RUNX1, TP53, and CEBPA mutations PMID:23634996
  • Mutations in 28% (n=436) of AML; class-defining for the largest subgroup; favorable as monotherapy but outcome strongly modified by co-occurring FLT3, DNMT3A, IDH2, NRAS, PTPN11, and chromatin-spliceosome mutations; allogeneic transplant decisions should integrate co-mutation profiles PMID:27276561

Cancer types (linked)

  • AML (Acute Myeloid Leukemia): Mutated in 27% of adult de novo AML; defines an epigenetically distinct intermediate-risk subtype when co-occurring with DNMT3A and FLT3 mutations; already incorporated into AML classification schemes PMID:23634996

Co-occurrence and mutual exclusivity

Therapeutic relevance

  • The concurrent NPM1 + DNMT3A + FLT3 genotype, combined with distinct mRNA, miRNA, and CpG-sparse methylation signatures, may define a novel intermediate-risk AML subtype warranting separate classification and therapy stratification PMID:23634996

Open questions

  • Whether the NPM1 + DNMT3A + FLT3 triple-mutant subtype has a distinct prognosis relative to individual pairwise co-mutations requires prospective validation in larger cohorts PMID:23634996

Sources

This page was processed by entity-page-writer on 2026-05-15. - PMID:27276561

This page was processed by entity-page-writer on 2026-05-15.