NRAS mutation causes a human autoimmune lymphoproliferative syndrome

The p21 RAS subfamily of small GTPases, including KRAS, HRAS, and NRAS, regulates cell proliferation, cytoskeletal organization, and other signaling networks, and is the most frequent target of activating mutations in cancer. Activating germline mutations of KRAS and HRAS cause severe developmental abnormalities leading to Noonan, cardio-facial-cutaneous, and Costello syndrome, but activating germline mutations of NRAS have not been reported. Autoimmune lymphoproliferative syndrome (ALPS) is the most common genetic disease of lymphocyte apoptosis and causes autoimmunity as well as excessive lymphocyte accumulation, particularly of CD4−, CD8− αβ T cells. Mutations in ALPS typically affect CD95 (Fas/APO-1)-mediated apoptosis, one of the extrinsic death pathways involving TNF receptor superfamily proteins, but certain ALPS individuals have no such mutations. We show here that the salient features of ALPS as well as a predisposition to hematological malignancies can be caused by a heterozygous germline Gly13Asp activating mutation of the NRAS oncogene that does not impair CD95-mediated apoptosis. The increase in active, GTP-bound NRAS augments RAF/MEK/ERK signaling, which markedly decreases the proapoptotic protein BIM and attenuates intrinsic, nonreceptor-mediated mitochondrial apoptosis. Thus, germline activating mutations in NRAS differ from other p21 Ras oncoproteins by causing selective immune abnormalities without general developmental defects. Our observations on the effects of NRAS activation indicate that RAS-inactivating drugs, such as farnesyltransferase inhibitors should be examined in human autoimmune and lymphocyte homeostasis disorders.

[1]  C. Marshall,et al.  Amino-acid substitutions at codon 13 of the N-ras oncogene in human acute myeloid leukaemia , 1985, Nature.

[2]  N-ras gene point mutations in childhood acute lymphocytic leukemia correlate with a poor prognosis. , 1990 .

[3]  E. Jaffe,et al.  A novel lymphoproliferative/autoimmune syndrome resembling murine lpr/gld disease. , 1992, The Journal of clinical investigation.

[4]  F. Rieux-Laucat,et al.  Mutations in Fas associated with human lymphoproliferative syndrome and autoimmunity. , 1995, Science.

[5]  Warren Strober,et al.  Dominant interfering fas gene mutations impair apoptosis in a human autoimmune lymphoproliferative syndrome , 1995, Cell.

[6]  P. Schur,et al.  Fas ligand mutation in a patient with systemic lupus erythematosus and lymphoproliferative disease. , 1996, The Journal of clinical investigation.

[7]  R. Kucherlapati,et al.  K-ras is an essential gene in the mouse with partial functional overlap with N-ras. , 1997, Genes & development.

[8]  J. Puck,et al.  Inherited Human Caspase 10 Mutations Underlie Defective Lymphocyte and Dendritic Cell Apoptosis in Autoimmune Lymphoproliferative Syndrome Type II , 1999, Cell.

[9]  A. Strasser,et al.  Proapoptotic Bcl-2 relative Bim required for certain apoptotic responses, leukocyte homeostasis, and to preclude autoimmunity. , 1999, Science.

[10]  J. Puck,et al.  Immunophenotypic profiles in families with autoimmune lymphoproliferative syndrome. , 2001, Blood.

[11]  M. Malumbres,et al.  Targeted Genomic Disruption of H-ras and N-ras, Individually or in Combination, Reveals the Dispensability of Both Loci for Mouse Growth and Development , 2001, Molecular and Cellular Biology.

[12]  J. Puck,et al.  TcR-alpha/beta(+) CD4(-)CD8(-) T cells in humans with the autoimmune lymphoproliferative syndrome express a novel CD45 isoform that is analogous to murine B220 and represents a marker of altered O-glycan biosynthesis. , 2001, Clinical immunology.

[13]  I. Vetter,et al.  The Guanine Nucleotide-Binding Switch in Three Dimensions , 2001, Science.

[14]  Thomas D. Schmittgen,et al.  Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. , 2001, Methods.

[15]  M. Malumbres,et al.  Mice deficient for N-ras: impaired antiviral immune response and T-cell function. , 2003, Cancer research.

[16]  S. Cook,et al.  Activation of the ERK1/2 Signaling Pathway Promotes Phosphorylation and Proteasome-dependent Degradation of the BH3-only Protein, Bim* , 2003, Journal of Biological Chemistry.

[17]  M. Barbacid,et al.  RAS oncogenes: the first 30 years , 2003, Nature Reviews Cancer.

[18]  S. Korsmeyer,et al.  Cell Death Critical Control Points , 2004, Cell.

[19]  J. B. Oliveira,et al.  Autoimmune lymphoproliferative syndrome , 2004, Current opinion in allergy and clinical immunology.

[20]  F. Rieux-Laucat,et al.  Autoimmune lymphoproliferative syndrome with somatic Fas mutations. , 2004, The New England journal of medicine.

[21]  S. Cook,et al.  Extracellular Signal-regulated Kinases 1/2 Are Serum-stimulated “BimEL Kinases” That Bind to the BH3-only Protein BimEL Causing Its Phosphorylation and Turnover* , 2004, Journal of Biological Chemistry.

[22]  A. Strasser,et al.  T-lymphocyte death during shutdown of an immune response. , 2004, Trends in immunology.

[23]  S. Cook,et al.  Regulatory phosphorylation of Bim: sorting out the ERK from the JNK , 2005, Cell Death and Differentiation.

[24]  E. White,et al.  Key roles of BIM-driven apoptosis in epithelial tumors and rational chemotherapy. , 2005, Cancer cell.

[25]  F. McCormick,et al.  Cancer targets in the Ras pathway. , 2005, Cold Spring Harbor symposia on quantitative biology.

[26]  A. Strasser The role of BH3-only proteins in the immune system , 2005, Nature Reviews Immunology.

[27]  D. Schadendorf,et al.  Effect of common B-RAF and N-RAS mutations on global gene expression in melanoma cell lines. , 2005, Carcinogenesis.

[28]  Yukichi Tanaka,et al.  Germline mutations in HRAS proto-oncogene cause Costello syndrome , 2005, Nature Genetics.

[29]  J. Karp,et al.  Targeting the process of farynesylation for therapy of hematologic malignancies. , 2005, Current molecular medicine.

[30]  M. Lenardo,et al.  Caspase-8 Regulation by Direct Interaction with TRAF6 in T Cell Receptor-Induced NF-κB Activation , 2006, Current Biology.

[31]  Bruce D Gelb,et al.  Noonan syndrome and related disorders: dysregulated RAS-mitogen activated protein kinase signal transduction. , 2006, Human molecular genetics.

[32]  M. Philips,et al.  Compartmentalized Ras/MAPK signaling. , 2006, Annual review of immunology.

[33]  M. Lenardo,et al.  Genetic disorders of programmed cell death in the immune system. , 2006, Annual review of immunology.

[34]  Kam Y. J. Zhang,et al.  Germline KRAS mutations cause Noonan syndrome , 2006, Nature Genetics.

[35]  A. Anel,et al.  A homozygous Fas ligand gene mutation in a patient causes a new type of autoimmune lymphoproliferative syndrome. , 2006, Blood.

[36]  Pablo Rodriguez-Viciana,et al.  Germline Mutations in Genes Within the MAPK Pathway Cause Cardio-facio-cutaneous Syndrome , 2006, Science.

[37]  R. Hennekam,et al.  Germline KRAS and BRAF mutations in cardio-facio-cutaneous syndrome , 2006, Nature Genetics.

[38]  Wendy Schackwitz,et al.  Gain-of-function SOS1 mutations cause a distinctive form of Noonan syndrome , 2006, Nature Genetics.

[39]  J. Puck,et al.  Dominant inhibition of Fas ligand-mediated apoptosis due to a heterozygous mutation associated with autoimmune lymphoproliferative syndrome (ALPS) Type Ib , 2007, BMC Medical Genetics.