title: Translocations and mutations involving the nucleophosmin (NPM1) gene in lymphomas and leukemias.
abstract: Nucleophosmin (NPM) is a ubiquitously expressed nucleolar phoshoprotein which shuttles continuously between the nucleus and cytoplasm. Many findings have revealed a complex scenario of NPM functions and interactions, pointing to proliferative and growth-suppressive roles of this molecule. The gene NPM1 that encodes for nucleophosmin (NPM1) is translocated or mutated in various lymphomas and leukemias, forming fusion proteins (NPM-ALK, NPM-RARalpha, NPM-MLF1) or NPM mutant products. Here, we review the structure and functions of NPM, as well as the biological, clinical and pathological features of human hematologic malignancies with NPM1 gene alterations. NPM-ALK indentifies a new category of T/Null lymphomas with distinctive molecular and clinico-pathological features, that is going to be included as a novel disease entity (ALK+ anaplastic large cell lymphoma) in the new WHO classification of lymphoid neoplasms. NPM1 mutations occur specifically in about 30% of adult de novo AML and cause aberrant cytoplasmic expression of NPM (hence the term NPMc+ AML). NPMc+ AML associates with normal karyotpe, and shows wide morphological spectrum, multilineage involvement, a unique gene expression signature, a high frequency of FLT3-internal tandem duplications, and distinctive clinical and prognostic features. The availability of specific antibodies and molecular techniques for the detection of NPM1 gene alterations has an enormous impact in the biological study diagnosis, prognostic stratification, and monitoring of minimal residual disease of various lymphomas and leukemias. The discovery of NPM1 gene alterations also represents the rationale basis for development of molecular targeted drugs.
authors.affiliation: Section of Haematology and Immunology, University of Perugia, IBit Foundation, Perugia, Italy. faliniem@unipg.it
authors.forename: Brunangelo
authors.initials: B
authors.lastname: Falini
authors.forename: Ildo
authors.initials: I
authors.lastname: Nicoletti
authors.forename: Niccolò
authors.initials: N
authors.lastname: Bolli
authors.forename: Maria Paola
authors.initials: MP
authors.lastname: Martelli
authors.forename: Arcangelo
authors.initials: A
authors.lastname: Liso
authors.forename: Paolo
authors.initials: P
authors.lastname: Gorello
authors.forename: Franco
authors.initials: F
authors.lastname: Mandelli
authors.forename: Cristina
authors.initials: C
authors.lastname: Mecucci
authors.forename: Massimo Fabrizio
authors.initials: MF
authors.lastname: Martelli
mesh_terms: D000208:Acute Disease; D000328:Adult; D017668:Age of Onset; D017398:Alternative Splicing; D020816:Amino Acid Motifs; D001692:Biological Transport; D002466:Cell Nucleolus / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism; D002648:Child; D002895:Chromosomes, Human, Pair 5 / Q000235:genetics; D003593:Cytoplasm / Q000378:metabolism; D006801:Humans; D007621:Karyotyping; D007951:Leukemia, Myeloid / Q000175:diagnosis / Q000188:drug therapy / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology; D017728:Lymphoma, Large-Cell, Anaplastic / Q000175:diagnosis / Q000188:drug therapy / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology; D009154:Mutation; D009363:Neoplasm Proteins / Q000235:genetics / Q000502:physiology; D009687:Nuclear Proteins / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D000090243:Nucleophosmin; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000502:physiology; D011379:Prognosis; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000502:physiology; D012270:Ribosomes / Q000378:metabolism; D013329:Structure-Activity Relationship; D014178:Translocation, Genetic; D016896:Treatment Outcome
chemical_list: C120078:NPM-MLF1 protein, human; C120276:NPM-RARalpha protein, human; C000716967:NPM1 protein, human; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D015514:Oncogene Proteins, Fusion; D000090243:Nucleophosmin; C107023:p80(NPM-ALK) protein; D011505:Protein-Tyrosine Kinases