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Medline ® Abstract for Reference 49

of 'Autoimmune lymphoproliferative syndrome (ALPS): Clinical features and diagnosis'

49
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Somatic KRAS mutations associated with a human nonmalignant syndrome of autoimmunity and abnormal leukocyte homeostasis.
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Niemela JE, Lu L, Fleisher TA, Davis J, Caminha I, Natter M, Beer LA, Dowdell KC, Pittaluga S, Raffeld M, Rao VK, Oliveira JB
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Blood. 2011;117(10):2883. Epub 2010 Nov 15.
 
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.
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Department of Laboratory Medicine, Warren Grant Magnuson Clinical Center, Bethesda, MD, USA. oliveirajb@cc.nih.gov
PMID