Autoimmune lymphoproliferative syndrome–like disease with somatic KRAS mutation

Takagi, Motoki; Shinoda, Kei; Piao, Jinhua; Mitsuiki, Noriko; Takagi, Mari; Matsuda, Kazuyuki; Muramatsu, Hideki; Doisaki, Sayoko; Nagasawa, Mitsuru; Morio, Tomohiro; Kasahara, Yoshihito; Koike, Kenichi; Kojima, Seiji; Takao, Akira; Mizutani, Shuki

doi:10.1182/blood-2010-08-301515

Cited by 125 publications

(89 citation statements)

References 19 publications

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“…Ras is therefore a positive regulator of TLR responses in vitro. Furthermore, the in vivo relevance of these observations is supported by the involvement of Ras in a rare type of autoimmunity (34,35). These two mechanisms: the promotion of endosomal maturation and the suppression of Ras signaling, are not mutually exclusive.…”

Section: Discussionmentioning

confidence: 58%

Rabex-5 is a lenalidomide target molecule that negatively regulates TLR-induced type 1 IFN production

Millrine

Tei

Gemechu

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Immunomodulatory drugs (IMiDs) are a family of compounds derived from thalidomide. Binding of the IMiD molecule to the Lon protease Cereblon initiates the degradation of substrates via the ubiquitin proteasome pathway. Here, we show that Cereblon forms a complex with Rabex-5, a regulator of immune homeostasis. Treatment with lenalidomide prevented the association of Cereblon with Rabex-5. Conversely, mutation of the IMiD binding site increased Cereblon–Rabex-5 coimmunoprecipitation. The thalidomide binding region of Cereblon therefore regulates the formation of this complex. Knockdown of Rabex-5 in the THP-1 macrophage cell line up-regulated Toll-like receptor (TLR)-induced cytokine and type 1 IFN production via a STAT1/IRF activating pathway. Thus, we identify Rabex-5 as a IMiD target molecule that functions to restrain TLR activated auto-immune promoting pathways. We propose that release of Rabex-5 from complex with Cereblon enables the suppression of immune responses, contributing to the antiinflammatory properties of IMiDs.

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Section: Discussionmentioning

confidence: 58%

Rabex-5 is a lenalidomide target molecule that negatively regulates TLR-induced type 1 IFN production

Millrine

Tei

Gemechu

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…72 Other investigators agreed that, indeed, an occasional patient with JMML and NRAS mutations had spontaneous resolution of their myeloproliferative disorder despite persistence of the NRAS mutation in hematopoietic cells. 44,70 However, there was no specific genotype-phenotype correlation for the different RAS codons. Doisaki et al claimed that 2 of their patients with JMML, NRAS mutation and a mild and selflimiting course had somatic mosaicism of their oncogenic NRAS mutations.…”

Section: CM Niemeyer Et Almentioning

confidence: 99%

“…67,68 There is a puzzling interface between KRAS-associated lymphoproliferative disease (RALD) and JMML with KRAS mutation. 69,70 Individuals affected by RALD show overexpansion of lymphocytes with hepatosplenomegaly, lymphadenopathy and autoimmune phenomena like autoimmune hemolytic anemia, thrombocytopenia (Evan's syndrome) and neutropenia. Lanzarotti et al recently presented a case with RALD as initial presentation at five years of age and fatal JMML at 20 years of age.…”

Section: CM Niemeyer Et Almentioning

confidence: 99%

RAS diseases in children

Niemeyer

2014

Haematologica

113

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REVIEW ARTICLES 1653 IntroductionDiscoveries made about 50 years ago revealed the transforming power of the Harvey and Kirsten murine sarcoma retroviruses by a set of genes named RAS genes for their role in forming rat sarcomas. Subsequently, the contribution of RAS genes to cancer pathogenesis has been studied extensively. While the somatic dysregulation of RAS is a primary driver of cancer, there is a class of developmental disorders caused by germline mutations (as opposed to the somatic mutations found in cancer) in genes that encode components of the RAS signaling pathway. This chapter summarizes hematologic disturbances and cancer predisposition of these genetic disorders named "RASopathies". It will focus on juvenile myelomonocytic leukemia (JMML), an infant leukemia with initiating germline and somatic mutations in genes of the RAS signal transduction pathway. RAS and the RAS/mitogen-activated protein kinase signaling cascadeRAS turned out to be an essential cellular hub for a wide variety of signaling pathways including the three human RAS genes, KRAS, NRAS and HRAS (reviewed by Stephen et al. 1). RAS proteins act as molecular switches by cycling between an active guanosine triphospate (GTP)-bound (RAS-GTP) and an inactive guanosine diphosphate (GDP)-bound (RAS-GDP) conformation (Figure 1).2 RAS-GTP concentrations are tightly regulated by the competitive action of guanosin exchange factors (GEFs) and GTPase activating proteins (GAPs).RAS is activated by extracellular stimuli such as growth factor binding to receptor tyrosine kinases (RTKs) followed by RTK autophosphorylation and the creation of docking sites for adaptor molecules (e.g. GRB2). These molecules recruit and activate GEFs (e.g. SOS1) which displace GDP from RAS allowing RAS to bind to GTP. RAS-GTP binds to and activates a large number of effector pathways. The RAS-mediated mitogen-activated kinase (MAPK) pathway is one of several important downstream cascades. Activated RAS binds to RAF (RAF1, also known as CRAF, BRAF), the first MAPK of the signaling cascade. RAF phosphorylates MEK1 and/or MEK2, which in turn activate ERK1 and/or ERK2. Active ERKs serve as regulators of a large number of downstream processes both in the cytosol and nucleus.

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“…These cases are not classified as ALPS, because caspase-8 deficiency state is additionally characterized by disturbed T-cell activation and immunodeficiency and RAS-associated ALPS-like disease by monocytosis. [18][19][20][21] For 20-30% of patients with the clinical picture of ALPS, however, the genetic cause is still unknown (termed ALPS-U cases). 2 It is plausible that Fas pathway regulating factors may present novel candidates causing ALPS and potential drug targets.…”

Section: Introductionmentioning

confidence: 99%

Deregulation of Fas ligand expression as a novel cause of autoimmune lymphoproliferative syndrome-like disease

et al. 2015

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© F e r r a t a S t o r t i F o u n d a t i o nFor instance, forced expression of the Fas regulating miR146a caused an immune disorder similar to ALPS in transgenic mice. 22 One factor known to regulate expression of both Fas and FasL is interleukin-12 (IL12). [23][24][25][26][27][28][29][30] This cytokine mediates its effects via binding to a heterodimeric receptor composed of the IL12 receptors β1 (IL12RB1) and β2 (IL12RB2) and subsequent activation of JAK/STAT signaling. 31 The IL12 receptor is mainly expressed on T lymphocytes and natural killer (NK) cells. IL12RB1 deficiency is associated with Mendelian susceptibility to mycobacterial diseases. [32][33][34][35] These diseases predispose affected individuals to mycobacterial infections (tuberculosis) due to disturbance of IL12/IL23/IFNg signaling. IL12RB1 also associates with IL23R to form the IL23 receptor. Phagocytic cells release both IL12 and IL23 in response to non-viral infections to induce the secretion of interferon (IFN)g by T and NK cells. This in turn stimulates phagocytes to eliminate intracellular pathogens and activation of IFNg−secreting T helper cells. The IL12 signaling pathway is known to regulate FasL expression on activated T cells and knockout of IL12RB2 predisposes mice to spontaneous autoimmunity, lymphoproliferation and B-cell malignancies. 36 In the present study we identified a patient with a classical ALPS phenotype that was associated with a truncating nonsense mutation in IL12RB1 and loss of IL12/IL23-mediated signaling. Methods Study cohorts and DNA isolationTwenty-six ALPS patients, relatives and healthy controls were enrolled in the study. Written informed consent was obtained from all participants. Experiments were approved by the Ethical Review Boards of Hadassah, the Israeli Ministry of Health and the local Ethics committee of the University of Düsseldorf. Mononuclear cells were derived from peripheral blood by Ficoll (Biochrom, Berlin, Germany) density centrifugation. DNT cells were magnetically selected employing the double-negative T-cell isolation kit (Miltenyi, Bergisch-Gladbach, Germany). Genomic DNA was isolated from whole blood or DNT cells using the DNA blood kit (Qiagen, Hilden, Germany). Whole-exome sequencing and data analysisAfter exclusion of mutations in known ALPS-associated genes by targeted Sanger sequencing (Online Supplementary Methods, Online Supplementary Table S1) whole-exome sequencing was carried out as described elsewhere. 37 In brief, sequencing libraries of 350 bp fragments were generated from sheared genomic DNA. Exome capture was performed using the SeqCap EZ Exome Library 2.0 kit (Roche/Nimblegen, Madison, WI, USA). One hundred base-pair, single-read sequencing was performed on a HiSeq2000 (Illumina, San Diego, CA, USA).Sequencing data were aligned against the human reference genome hg19 (GRCh37, statistics provided in Online Supplementary Table S2) and converted using Samtools. 38 Variation calls were obtained employing GATK, HapMap, OmniArray and dbSNP134 datasets (The Broad Institu...

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Autoimmune lymphoproliferative syndrome–like disease with somatic KRAS mutation

Cited by 125 publications

References 19 publications

Rabex-5 is a lenalidomide target molecule that negatively regulates TLR-induced type 1 IFN production

Rabex-5 is a lenalidomide target molecule that negatively regulates TLR-induced type 1 IFN production

RAS diseases in children

Deregulation of Fas ligand expression as a novel cause of autoimmune lymphoproliferative syndrome-like disease

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