title: Somatic KRAS mutations associated with a human nonmalignant syndrome of autoimmunity and abnormal leukocyte homeostasis.
abstract: Somatic gain-of-function mutations in members of the RAS subfamily of small guanosine triphosphatases are found in > 30% of all human cancers. We recently described a syndrome of chronic nonmalignant lymphadenopathy, splenomegaly, and autoimmunity associated with a mutation in NRAS affecting hematopoietic cells, and initially we classified the disease as a variant of the autoimmune lymphoproliferative syndrome. Here, we demonstrate that somatic mutations in the related KRAS gene can also be associated with a nonmalignant syndrome of autoimmunity and breakdown of leukocyte homeostasis. The activating KRAS mutation impaired cytokine withdrawal-induced T-cell apoptosis through the suppression of the proapoptotic protein BCL-2 interacting mediator of cell death and facilitated proliferation through p27(kip1) down-regulation. These defects could be corrected in vitro by mitogen-activated protein kinase/extracellular signal-regulated kinase kinase 1 or phosphatidyl inositol-3 kinase inhibition. We suggest the use of the term RAS-associated autoimmune leukoproliferative disease to differentiate this disorder from autoimmune lymphoproliferative syndrome.
authors.affiliation: Department of Laboratory Medicine, Warren Grant Magnuson Clinical Center, Bethesda, MD, USA. oliveirajb@cc.nih.gov
authors.forename: Julie E
authors.initials: JE
authors.lastname: Niemela
authors.forename: Lianghao
authors.initials: L
authors.lastname: Lu
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Fleisher
authors.forename: Joie
authors.initials: J
authors.lastname: Davis
authors.forename: Iusta
authors.initials: I
authors.lastname: Caminha
authors.forename: Marc
authors.initials: M
authors.lastname: Natter
authors.forename: Laurel A
authors.initials: LA
authors.lastname: Beer
authors.forename: Kennichi C
authors.initials: KC
authors.lastname: Dowdell
authors.forename: Stefania
authors.initials: S
authors.lastname: Pittaluga
authors.forename: Mark
authors.initials: M
authors.lastname: Raffeld
authors.forename: V Koneti
authors.initials: VK
authors.lastname: Rao
authors.forename: João B
authors.initials: JB
authors.lastname: Oliveira
mesh_terms: D001327:Autoimmune Diseases / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D015551:Autoimmunity / Q000235:genetics; D001483:Base Sequence; D002469:Cell Separation; D002648:Child; D002675:Child, Preschool; D005260:Female; D005434:Flow Cytometry; D006706:Homeostasis / Q000235:genetics / Q000276:immunology; D006801:Humans; D007160:Immunoproliferative Disorders / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D007962:Leukocytes / Q000276:immunology / Q000473:pathology*; D008969:Molecular Sequence Data; D009154:Mutation; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D016283:Proto-Oncogene Proteins p21(ras); D013577:Syndrome; D018631:ras Proteins / Q000235:genetics*
chemical_list: C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins