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IL7R (interleukin 7 receptor)

Identity

Other namesCD127
CDW127
IL-7R-alpha
IL7RA
ILRA
HGNC (Hugo) IL7R
LocusID (NCBI) 3575
Location 5p13.2
Location_base_pair Starts at 35856977 and ends at 35879705 bp from pter ( according to hg19-Feb_2009)

DNA/RNA

 
  IL7R gene. The gene is composed of 8 exons highlighted in dark green. The 5' and 3' untranslated regions (UTR) are highlighted in light green.
Transcription The gene is composed of 8 exons. The canonical transcript is 4619 bp long. Alternative splicing generates a soluble isoform lacking exon 6 and introducing a premature stop codon (Goodwin et al., 1990; Rose et al., 2009).
Pseudogene No pseudogene.

Protein

 
  IL-7Rα protein. This receptor belongs to the type-I cytokine receptor family. In the extracellular domain, it displays 4 paired cysteines (represented in yellow) in 2 fibronectin type III-like domains and, closer to the transmembrane domain, a WSxWS motif. The intracellular domain has a Box 1 motif and at least 2 tyrosines (Y401, Y449) involved in signal transduction (Lin et al., 1995; Venkitaraman and Cowling, 1994).
Description The precursor IL-7Rα protein includes a signal peptide (20 aminoacids) and has 459 aminoacids in total. The mature protein undergoes several post-translational modifications including glycosylation (6 potential N-glycosylation sites in the extracellular domain) and dissulfide bond formation. The extracellular domain has 219 aminoacids (spanning from aminoacids 21 to 239), the transmembrane domain has 25 aminoacids (spanning from aminoacids 240 to 264), and the cytoplasmic tail spans from aminoacids 265 - 459 (195 aminoacids). The soluble isoform of the receptor lacks the transmembrane domain (exon 6) and, due to an altered translation reading frame, it thereafter contains 27 unique aminoacids in the C-terminus (Goodwin et al., 1990; Rose et al., 2009).
Expression IL-7Rα expression and signaling is required for normal T-cell development and homeostasis (Puel et al., 1998; Ribeiro et al., 2013). Although IL-7 signaling is not required for normal human B-cell development (in contrast to the mouse, where it is fundamental) IL-7Rα is also expressed in B-cell precursors (Mazzucchelli and Durum, 2007).
Localisation The functional protein is localized at the plasma membrane where it forms an heterodimeric complex with the common gamma chain (IL-2Rγ, CD132) to transduce IL-7 signaling or the cytokine receptor-like factor 2/ thymic stromal lymphopoietin receptor (CRLF2/TSLPR) to transduce TSLP signaling. IL-7Rα endocytosis via clathrin-coated pits appears to be required for maximal IL-7-mediated signaling (Henriques et al., 2010).
Function IL-7Rα mediates the signaling of IL-7 and TSLP cytokines. The cytoplasmic tail of IL-7R associates directly with JAK1 to transduce intracellular signaling together with JAK3 or JAK2 that are associated with the IL-2Rγ or TSLPR, respectively. The intracellular signaling pathways activated upon IL-7/IL-7R engagement in T-cells are the JAK/STAT (Lin et al., 1995; Rosenthal et al., 1997), PI3K/Akt/mTOR (Dadi and Roifman, 1993; Venkitaraman and Cowling, 1994; Rathmell et al., 2001) and, in some instances, MEK/Erk (Fleming and Paige, 2001; Maki and Ikuta, 2008; Patel and Chang, 2012).
IL-7/IL-7R signaling is required for T-cell development at different stages. At the double-negative stage (DN; CD4- CD8-), it is required for survival and proliferation of T-cells. It is also required to initiate the recombination of the TCRγ locus (Ye et al., 2001), the reason why it is absolutely required for γδ T-cell development. The receptor is down-regulated at the double-positive stage (DP; CD4+ CD8+) and up-regulated again at the single-positive stage (SP; CD4+ or CD8+). At this stage, IL-7R appears to be involved in CD4 versus CD8 lineage specification (at least in the mouse, possibly in humans) and overall cell survival (Park et al., 2010; Sinclair et al., 2011). Mature T-cells also benefit from IL-7R signaling for homeostatic maintenance and function (Soares et al., 1998).
The function of the TSLP/IL-7R signaling is much less known. Most studies, suggest an important role in the normal function of dendritic cells, immune tolerance and allergy (Watanabe et al., 2005; Lee et al., 2008; reviewed in Ziegler, 2012 and Hanabuchi et al., 2012).
Homology IL-7R displays aminoacid sequence identity with other human cytokine receptors, such as IL-2R (14.6%), IL-6R (13.2%) GM-CSF receptor (16.0%) GH receptor (12.9%) (Goodwin et al., 1990).
Orthologs of the human IL-7R are found in other species. The murine Il7r has 64%/67.2% DNA/protein identity (Goodwin et al., 1990) and the zebrafish il7r has 20.5% protein identity (Liongue and Ward, 2007) compared with the human receptor.

Mutations

 
  IL-7Rα mutational hotspot for gain-of-function mutations. The figure depicts the 3 major domains of the IL-7R with the mutational hotspots present. The T-ALL mutations are restricted to exon 6 (coding for the transmembrane domain) and affect the juxtamembrane-transmembrane region (yellow lightning bolts). B-ALL mutations, although rarer, can also affect exon 5 (S185C; red lightning bolt).
Germinal Hereditary recessive inactivating mutations in the IL7R gene have been found to cause severe combined immunodeficiency (SCID)(Puel et al., 1998; Roifman et al., 2000; Jo et al., 2004; Giliani et al., 2005). The mutations occur in the extracellular domain coding region and comprise missense, nonsense mutations and splicing affecting mutations. The IL-7R SCID is characterized as T-B+NK+. The treatment is hematopoietic stem cell transplantation.
Somatic Somatic and heterozygous IL7R gain-of-funtion gene mutations have been found in around 9-10% of childhood T-cell acute lymphoblastic leukemia (T-ALL) cases (Zenatti et al., 2011; Shochat et al., 2011; Zhang et al., 2012). Later, mutations in the IL7R in adult T-ALL (1.7%) were also found (Kim et al., 2013). So far, all T-ALL mutations described are restricted to exon 6, affecting the extracellular juxtamembrane-transmembrane domain of the protein. The mutations are in-frame insertions or deletions-insertions. The majority include an unpaired cysteine addition responsible for the homodimerization of two IL7-Rα chains via disulphide bond formation. The dimerization of the receptor leads to ligand-independent constitutive signaling via JAK1 (Zenatti et al., 2011), contrasting with the physiological heterodimeric IL-7-dependent activation of the receptor that additionally requires IL-2Rγ and JAK3.
IL7R somatic, heterozygous mutations have also been described in a small fraction of B-cell ALL (B-ALL) cases (less than 1%), significantly associated with aberrant TSLPR expression (Shochat et al., 2011). These included similar mutations to those found in T-ALL, as well as, in half of the cases, mutations in exon 5 leading to an S185C aminoacid substitution (Shochat et al., 2011).

Implicated in

Entity Severe combined immunodeficiency (SCID)
Disease IL-7R SCID of T-B+NK+ type results from loss-of-function mutations. For further details see the Mutations section.
Prognosis IL-7R SCID is a fatal disease. The treatment is bone marrow transplantation.
  
Entity T-cell acute lymphoblastic leukemia (T-ALL)
Prognosis IL7R mutations are not associated with prognosis (Zenatti et al., 2011). Increased IL-7 responsiveness in vitro was associated with better initial response to treatment in vivo (Karawajew et al., 2000). Low expression of IL-7R was found correlated with poor prognosis (Cleaver et al., 2010).
Oncogenesis IL-7/IL-7R signaling has a major impact in the survival and proliferation of T-ALL cells in vitro (e.g. Touw et al., 1990; Dibirdik et al., 1991; Barata et al., 2004a; Barata et al., 2004b) and leukemia expansion in vivo (Silva et al., 2011).
Oncogenic IL7R activating mutations occur in T-ALL. See the Mutations section for details.
Truncated forms of the IL-7R originated by alternative splicing were found in childhood T-ALL primary samples (Korte et al., 2000). The truncated receptors still bind IL-7 and it was postulated, but not functionally demonstrated, that they might modulate IL-7 downstream signaling.
  
Entity B-cell acute lymphoblastic leukemia (B-ALL)
Oncogenesis IL-7R mutations occur in B-ALL. See the Mutations section for details.
Expression of survival and proliferation markers is associated with CD127+ B-ALLs vs CD127- B-ALLs (Sasson et al., 2010).
  
Entity Chronic lymphocytic leukemia (CLL)
Oncogenesis IL-7 mRNA was detected in a whole cohort of 20 CLL primary samples (Frishman et al., 1993).
IL-7 was found to induce proliferation of CLL primary samples (Digel et al., 1991).
  
Entity Acute myeloid leukemia (AML)
Oncogenesis IL-7 was found to induce proliferation of AML primary samples (Digel et al., 1991).
An Exon 6 mutation in the IL7R gene was found in one case of adult AML (Kim et al., 2013). The functional impact of this mutation, which does not conform to the T-ALL or B-ALL type of mutations, was not evaluated.
  
Entity Hodgkin's lymphoma (HL)
Oncogenesis Both IL-7 and IL-7R proteins were found to be expressed in HL cell lines. An IL-7 autocrine loop was present that could sustain basal proliferation of these cells and the cells could further respond to exogenous added IL-7 (Cattaruzza et al., 2009).
  
Entity Cutaneous T-cell lymphoma (CTL)
Oncogenesis Both IL-7 and IL-7R expression was found in CTL primary samples (Foss et al., 1994). All 7 samples analyzed proliferated in the presence of IL-7. There was evidence for a possible autocrine loop.
  
Entity Breast cancer
Oncogenesis Both IL-7 and IL-7R were found to be expressed in some breast cancer cases. Patients with poorer prognosis had higher expression of both genes in the cancer tissue than those with better prognosis (Al-Rawi et al., 2004).
  
Entity Colorectal cancer
Oncogenesis IL-7 was found to be secreted in vitro by cultured colorectal cancer cell lines (2/4) and primary samples (16/18) (Maeurer et al., 1997).
Mutations in the exon 6 of the IL7R (0.5%) were found in a cohort of primary samples (Kim et al., 2013). However, these were frameshift mutations generating an early stop codon. Their functional impact was not evaluated.
  
Entity Esophageal cancer
Oncogenesis The expression levels of a small array of 21 cytokines in 6 esophageal cancer cell lines showed that IL-7 is expressed in 5 (Oka et al., 1995). Whether the IL-7R is also expressed remains to be investigated.
  
Entity Renal carcinoma
Oncogenesis Both IL-7 mRNA and protein were found to be secreted in renal carcinoma cell lines dependent on interferon gamma (IFNg) constitutive stimulation (Trinder et al., 1999).
In another study, IL-7R mRNA was found expressed in 2/7 renal carcinoma cell lines (Cosenza et al., 2002).
  
Entity Lung cancer
Prognosis High expression of IL-7R in tumor cells isolated from patients with stage I lung adenocarcinoma was predictive of poor overall outcome and increased probability of tumor recurrence (Suzuki et al., 2013).
Oncogenesis IL-7R mRNA and protein (3/7) were detected in lung cancer cell lines (Cosenza et al., 2002).
A missense mutation in the exon 6 of the IL7R was found in a member (0.6%) of a cohort of primary non-small cell lung cancer samples (Kim et al., 2013). The mutation does not conform to the type of mutations found in T-ALL or B-ALL. The functional impact of this mutation, which is unlikely to be gain-of-function, was not evaluated as yet.
  
Entity Multiple sclerosis
Disease A single nucleotide polymorphism at position 244(T/I) is associated with increased risk of mutiple sclerosis. T244 promotes increased exon 6 skipping leading to higher production of soluble IL7-Ra (Lundmark et al., 2007; Hafler et al., 2007). The role of the soluble form of the receptor in MS warrants investigation.
  
Entity Rheumatoid arthritis
Disease The 244(T/I) polymorphism was also found to be associated with rheumatoid arthritis risk (O'Doherty et al., 2009).
  
Entity Omenn syndrome (OS)
Disease A patient with OS, a SCID syndrome with graft-vesus-host disease symptoms, was found to have a mutation (C118Y) in the IL-7R (Giliani et al., 2006). This mutation was previously found correlated with SCID (Giliani et al., 2005).
  
Entity Allogeneic stem cell transplantation (SCT)
Note The single nucleotide polymorphism (SNPs) IL7Ra +1237 A/G (position) in the donors for SCT was found to correlate with survival of the recipient after SCT (Shamim et al., 2006).
  
Entity HIV infection
Disease Although the effects of IL-7/IL-7R during HIV infection on T-cells are well established, they are complex and still under heavy investigation. This entry only superficially covers some aspects of this relationship.
During HIV infection, T-cells have decreased IL-7R expression compared to healthy controls as well as decreased responsiveness to IL-7 (Carini et al., 1994; Vingerhoets et al., 1998).
The HIV Tat protein was found to be responsible for the downregulation of the receptor in CD8 T-cells (Faller et al., 2006).
The soluble IL-7R is increased in HIV+ individuals and can decrease the IL-7 activity in CD8 T-cells (Crawley et al., 2010).
Administration of IL-7 to HIV+ individuals under anti-retroviral therapy leads to an expansion of the T-cell compartment (Sereti et al., 2009; Levy et al., 2009) which may help to restore normal T-cell levels, however increased persistence of the virus in the affected individuals during therapy (Vandergeeten et al., 2013) may raise some concerns regarding the IL-7 therapy.
Comprehensive reviews on this topic include, but are not restricted to: Crawley and Angel, 2012; Sieg, 2012.
  

Other Leukemias implicated (Data extracted from papers in the Atlas)

Leukemias t0817q24q22ID1494 t1119q23p13ID1540

External links

Nomenclature
HGNC (Hugo)IL7R   6024
Cards
AtlasIL7RID51090ch5p13
Entrez_Gene (NCBI)IL7R  3575  interleukin 7 receptor
GeneCards (Weizmann)IL7R
Ensembl (Hinxton)ENSG00000168685 [Gene_View]  chr5:35856977-35879705 [Contig_View]  IL7R [Vega]
ICGC DataPortalENSG00000168685
cBioPortalIL7R
AceView (NCBI)IL7R
Genatlas (Paris)IL7R
WikiGenes3575
SOURCE (Princeton)NM_002185
Genomic and cartography
GoldenPath (UCSC)IL7R  -  5p13.2   chr5:35856977-35879705 +  5p13   [Description]    (hg19-Feb_2009)
EnsemblIL7R - 5p13 [CytoView]
Mapping of homologs : NCBIIL7R [Mapview]
OMIM146661   608971   
Gene and transcription
Genbank (Entrez)AA485865 AF373204 AK301220 AK315251 AL713738
RefSeq transcript (Entrez)NM_002185
RefSeq genomic (Entrez)AC_000137 NC_000005 NC_018916 NG_009567 NT_006576 NW_001838933 NW_004929321
Consensus coding sequences : CCDS (NCBI)IL7R
Cluster EST : UnigeneHs.591742 [ NCBI ]
CGAP (NCI)Hs.591742
Alternative Splicing : Fast-db (Paris)GSHG0023876
Alternative Splicing GalleryENSG00000168685
Gene ExpressionIL7R [ NCBI-GEO ]     IL7R [ SEEK ]   IL7R [ MEM ]
Protein : pattern, domain, 3D structure
UniProt/SwissProtP16871 (Uniprot)
NextProtP16871  [Medical]
With graphics : InterProP16871
Splice isoforms : SwissVarP16871 (Swissvar)
Domaine pattern : Prosite (Expaxy)FN3 (PS50853)    HEMATOPO_REC_S_F1 (PS01355)   
Domains : Interpro (EBI)Fibronectin_type3 [organisation]   Hempt_rcpt_S_F1_CS [organisation]   Ig-like_fold [organisation]  
Related proteins : CluSTrP16871
Domain families : Pfam (Sanger)fn3 (PF00041)   
Domain families : Pfam (NCBI)pfam00041   
DMDM Disease mutations3575
Blocks (Seattle)P16871
PDB (SRS)3DI2    3DI3    3UP1   
PDB (PDBSum)3DI2    3DI3    3UP1   
PDB (IMB)3DI2    3DI3    3UP1   
PDB (RSDB)3DI2    3DI3    3UP1   
Human Protein AtlasENSG00000168685 [gene] [tissue] [antibody] [cell] [cancer]
Peptide AtlasP16871
HPRD00893
IPIIPI00292014   IPI00419824   IPI00963850   IPI00216518   IPI00964765   IPI00965032   IPI00965711   IPI00968097   IPI00965330   IPI00964221   
Protein Interaction databases
DIP (DOE-UCLA)P16871
IntAct (EBI)P16871
FunCoupENSG00000168685
BioGRIDIL7R
InParanoidP16871
Interologous Interaction database P16871
IntegromeDBIL7R
STRING (EMBL)IL7R
Ontologies - Pathways
Ontology : AmiGOregulation of DNA recombination  cell morphogenesis  negative regulation of T cell mediated cytotoxicity  immunoglobulin production  antigen binding  interleukin-7 receptor activity  protein binding  extracellular region  plasma membrane  immune response  signal transduction  cell surface receptor signaling pathway  regulation of cell size  external side of plasma membrane  positive regulation of gene expression  integral component of membrane  cell growth  T cell differentiation  positive regulation of T cell differentiation in thymus  interleukin-7-mediated signaling pathway  B cell proliferation  lymph node development  homeostasis of number of cells  
Ontology : EGO-EBIregulation of DNA recombination  cell morphogenesis  negative regulation of T cell mediated cytotoxicity  immunoglobulin production  antigen binding  interleukin-7 receptor activity  protein binding  extracellular region  plasma membrane  immune response  signal transduction  cell surface receptor signaling pathway  regulation of cell size  external side of plasma membrane  positive regulation of gene expression  integral component of membrane  cell growth  T cell differentiation  positive regulation of T cell differentiation in thymus  interleukin-7-mediated signaling pathway  B cell proliferation  lymph node development  homeostasis of number of cells  
Pathways : BIOCARTAIL-7 Signal Transduction [Genes]   
Pathways : KEGGCytokine-cytokine receptor interaction    FoxO signaling pathway    PI3K-Akt signaling pathway    Jak-STAT signaling pathway    Hematopoietic cell lineage    Primary immunodeficiency   
Protein Interaction DatabaseIL7R
Wikipedia pathwaysIL7R
Gene fusion - rearrangments
Polymorphisms : SNP, mutations, diseases
SNP Single Nucleotide Polymorphism (NCBI)IL7R
snp3D : Map Gene to Disease3575
SNP (GeneSNP Utah)IL7R
SNP : HGBaseIL7R
Genetic variants : HAPMAPIL7R
Exome VariantIL7R
1000_GenomesIL7R 
ICGC programENSG00000168685 
Cancer Gene: CensusIL7R 
Somatic Mutations in Cancer : COSMICIL7R 
CONAN: Copy Number AnalysisIL7R 
Mutations and Diseases : HGMDIL7R
Genomic VariantsIL7R  IL7R [DGVbeta]
dbVarIL7R
ClinVarIL7R
Pred. of missensesPolyPhen-2  SIFT(SG)  SIFT(JCVI)  Align-GVGD  MutAssessor  Mutanalyser  
Pred. splicesGeneSplicer  Human Splicing Finder  MaxEntScan  
Diseases
OMIM146661    608971   
MedgenIL7R
GENETestsIL7R
Disease Genetic AssociationIL7R
Huge Navigator IL7R [HugePedia]  IL7R [HugeCancerGEM]
General knowledge
Homologs : HomoloGeneIL7R
Homology/Alignments : Family Browser (UCSC)IL7R
Phylogenetic Trees/Animal Genes : TreeFamIL7R
Chemical/Protein Interactions : CTD3575
Chemical/Pharm GKB GenePA29840
Clinical trialIL7R
Cancer Resource (Charite)ENSG00000168685
Other databases
Other databasehttp://cancergenome.broadinstitute.org/index.php?tgene=IL7R
Probes
Litterature
PubMed202 Pubmed reference(s) in Entrez
CoreMineIL7R
iHOPIL7R
OncoSearchIL7R

Bibliography

Cloning of the human and murine interleukin-7 receptors: demonstration of a soluble form and homology to a new receptor superfamily.
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Interleukin-7 is a growth factor of precursor B and T acute lymphoblastic leukemia.
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PMID 2189505
 
Engagement of interleukin-7 receptor stimulates tyrosine phosphorylation, phosphoinositide turnover, and clonal proliferation of human T-lineage acute lymphoblastic leukemia cells.
Dibirdik I, Langlie MC, Ledbetter JA, Tuel-Ahlgren L, Obuz V, Waddick KG, Gajl-Peczalska K, Schieven GL, Uckun FM.
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PMID 1650261
 
Human interleukin-7 induces proliferation of neoplastic cells from chronic lymphocytic leukemia and acute leukemias.
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Blood. 1991 Aug 1;78(3):753-9.
PMID 1859888
 
Activation of phosphatidylinositol-3 kinase by ligation of the interleukin-7 receptor on human thymocytes.
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Genes for interleukin 7 are transcribed in leukemic cell subsets of individuals with chronic lymphocytic leukemia.
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PMID 8459223
 
Dysregulation of interleukin-7 receptor may generate loss of cytotoxic T cell response in human immunodeficiency virus type 1 infection.
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PMID 7805718
 
Costimulation of cutaneous T-cell lymphoma cells by interleukin-7 and interleukin-2: potential autocrine or paracrine effectors in the Sezary syndrome.
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PMID 7522165
 
The role of shared receptor motifs and common Stat proteins in the generation of cytokine pleiotropy and redundancy by IL-2, IL-4, IL-7, IL-13, and IL-15.
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Interleukin-7 (IL-7) in colorectal cancer: IL-7 is produced by tissues from colorectal cancer and promotes preferential expansion of tumour infiltrating lymphocytes.
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IL-2 and IL-7 induce heterodimerization of STAT5 isoforms in human peripheral blood T lymphoblasts.
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PMID 9398404
 
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PMID 9843216
 
IL-7-dependent extrathymic expansion of CD45RA+ T cells enables preservation of a naive repertoire.
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J Immunol. 1998 Dec 1;161(11):5909-17.
PMID 9834071
 
Altered receptor expression and decreased sensitivity of T-cells to the stimulatory cytokines IL-2, IL-7 and IL-12 in HIV infection.
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PMID 9562375
 
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Int J Oncol. 1999 Jan;14(1):23-31.
PMID 9863005
 
Inhibition of in vitro spontaneous apoptosis by IL-7 correlates with bcl-2 up-regulation, cortical/mature immunophenotype, and better early cytoreduction of childhood T-cell acute lymphoblastic leukemia.
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Blood. 2000 Jul 1;96(1):297-306.
PMID 10891465
 
Expression analysis and characterization of alternatively spliced transcripts of human IL-7Ralpha chain encoding two truncated receptor proteins in relapsed childhood all.
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PMID 11052810
 
A partial deficiency of interleukin-7R alpha is sufficient to abrogate T-cell development and cause severe combined immunodeficiency.
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PMID 11023514
 
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PMID 11672535
 
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PMID 11739504
 
The IL-7 receptor controls the accessibility of the TCRgamma locus by Stat5 and histone acetylation.
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PMID 11728342
 
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PMID 11858939
 
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PMID 14962714
 
Common gamma chain-signaling cytokines promote proliferation of T-cell acute lymphoblastic leukemia.
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PMID 15590396
 
Activation of PI3K is indispensable for interleukin 7-mediated viability, proliferation, glucose use, and growth of T cell acute lymphoblastic leukemia cells.
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PMID 15353558
 
Characterization of a novel nonsense mutation in the interleukin-7 receptor alpha gene in a Korean patient with severe combined immunodeficiency.
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Written08-2013Daniel Ribeiro, João T Barata
Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal

Citation

This paper should be referenced as such :
Ribeiro D, Barata JT
IL7R (interleukin 7 receptor);
Atlas Genet Cytogenet Oncol Haematol. August 2013
Free online version   Free pdf version   [Bibliographic record ]
URL : http://AtlasGeneticsOncology.org/Genes/IL7RID51090ch5p13.html

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