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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. (Blood. 2010;117(10): 2883-2886) IntroductionThe autoimmune lymphoproliferative syndrome (ALPS) is characterized by childhood onset chronic lymphadenopathy, splenomegaly, multilineage cytopenias secondary to sequestration and autoimmune destruction, and an increased risk of B-cell lymphoma. 1 Laboratory findings include polyclonal hypergammaglobulinemia and expansion of a unique population of circulating T-cell receptor ␣␤ ϩ B220 ϩ CD4 Ϫ CD8 Ϫ T (␣␤ ϩ -DNT) lymphocytes. 2,3 Most patients with ALPS harbor heterozygous autosomaldominant germline mutations in FAS, with somatic FAS mutations representing the second most common genetic cause. [4][5][6][7] Germline mutations in the genes encoding FAS ligand and caspase 10 have been identified in a small minority of patients. [8][9][10][11][12] In our cohort, approximately one-third of the patients with ALPS have an undetermined genetic basis. In addition, there is a group of genetically undetermined ALPS-like patients without ␣␤ ϩ -DNT cell elevation.We recently reported one person among these latter patients with a syndrome of lymphoproliferation, autoimmunity, and minimally increased ␣␤ ϩ -DNT cells caused by a somatic mutation in the NRAS gene, resulting in defective lymphocyte apoptosis. 13 Here, we demonstrate that somatic mutations in the homologous KRAS gene can also be associated with a syndrome consisting of autoimmune phenomena and dysregulated leukocyte homeostasis, with normal ␣␤ ϩ -DNT cells. The activating KRAS mutation, like the previously described NRAS mutation, impaired intrinsic T-cell apoptosis through the suppression of the proapoptotic protein BCL-2 interacting mediator of cell death (BIM) and facilitated cellular proliferation by repression of p27 kip1 . Methods Cells and treatmentsAll patients were studied at the National Institutes of Health (NIH) under protocols approved by the institutional review b...