Somatic KRAS mutations associated with a human non-malignant syndrome of autoimmunity and abnormal leukocyte homeostasis

Wednesday, October 26, 2011 — Poster Session IV
2:00 p.m. – 4:00 p.m.	Natcher Conference Center	CC	IMMUNO/INFLAM-16

* FARE Award Winner

Authors

• L Lu
• JE Niemela
• TA Fleisher
• I Caminha
• J Davis
• MD Natter
• LA Beer
• KC Dowdell
• S Pittaluga
• M Raffeld
• VK Rao
• JB Oliveira

Abstract

Autoimmune lymphoproliferative syndrome (ALPS) is a non-malignant disease characterized by early-onset chronic lymphadenopathy, splenomegaly, multilineage cytopenias, polyclonal hypergammaglobulinemia, expansion of circulating TCRαβ+B220+CD4-CD8- T (αβ+-DNT) lymphocytes, and an increased risk of B-cell lymphoma. Most ALPS patients have germline or somatic TNFRSF6 (FAS) mutations, and a small minority of patients have germline mutations in the genes encoding FAS ligand and caspase 10. Somatic gain-of-function mutations in members of the RAS subfamily of small GTPases are found in > 30% of all human cancers. We recently reported that an ALPS-like phenotype can be caused by a somatic NRAS mutation (G13D) resulting in the defective lymphocyte apoptosis. Here we demonstrate that somatic mutations in the related KRAS gene can also be associated with a non-malignant syndrome of autoimmunity and breakdown of leukocyte homeostasis. The activating KRAS mutation (G13C) impaired cytokine-withdrawal induced T cell apoptosis through the suppression of the pro-apoptotic protein BIM and facilitated proliferation through p27kip1 downregulation. These defects could be corrected by MEK1 or PI3K inhibition in vitro. We suggest the use of the term RAS-associated autoimmune leukoproliferative disease (RALD) to differentiate this disorder from ALPS. The therapeutic targeting of signaling pathways downstream of RAS is a future option for these patients.

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