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LYL1 (lymphoblastic leukemia derived sequence 1)

Written2006-12Yuesheng Meng, Mark D. Minden
Department of Cellular and Molecular Biology, Ontario Cancer Institute/Princess Margaret Hospital, University Health Network, Toronto, Canada

(Note : for Links provided by Atlas : click)

Identity

Alias_nameslymphoblastic leukemia derived sequence 1
lymphoblastic leukemia associated hematopoiesis regulator 1
Alias_symbol (synonym)bHLHa18
Other alias
HGNC (Hugo) LYL1
LocusID (NCBI) 4066
Atlas_Id 51
Location 19p13.2  [Link to chromosome band 19p13]
Location_base_pair Starts at 13209842 and ends at 13213974 bp from pter ( according to hg19-Feb_2009)  [Mapping LYL1.png]
Fusion genes
(updated 2016)
LYL1 (19p13.2) / TAL1 (1p33)LYL1 (19p13.2) / TRB ()LYL1 (19p13.2) / TRBV20OR9-2 ()
TRB () / LYL1 (19p13.2)TRMU (22q13.31) / LYL1 (19p13.2)

DNA/RNA

Note DNA size: 3.83 kb; mRNA size: 1492 bp; Exons: 4.
 
Description Location of the LYL1 gene, identified by Non-random chromosomal translocation t(7;19)(q35;p13) associated with T-cell acute lymphoblastic leukemia (T-ALL), was mapped to the short arm of chromosome 19 (19p13) by in situ hybridization.
Transcription Expression levels of LYL1 are comparatively higher in normal bone marrow, spleen, lung, thymus and spinal cord tissues. Ectopic transcription is observed in T-lymphoblastic and myeloblastic leukemic cells.

Protein

Description LYL1 encodes a basic helix-loop-helix (bHLH) protein, with 267 amino acids and molecular weight of 28628 Da.
Localisation Subcellular location is potentially intracellular (nucleus). However, ectopic protein staining was observed in cytoplasm of myeloid leukemia cells with immunohistochemistry.
Function Recent studies show that LYL1 is required for fetal and adult hematopoietic stem cell function and B-cell differentiation. Overexpression of LYL1 is implicated in the pathogenesis of T-ALL as well as myeloid malignancies (see below, disease implications). The LYL1 protein is a transcription factor (TF), structurally and functionally similar to another bHLH protein TAL1/SCL which is also implicated in T-ALL. Expression of both LYL1 and TAL1/SCL are regulated by the Ets and GATA factors; However, ectopic expression of SCL but not Lyl1 can rescue haematopoietic differentiation in SCL(-/-) ES-cells, providing a molecular explanation for the vastly different phenotypes of SCL(-/-) and Lyl1(-/-) mouse embryos.
Efficient DNA binding of LYL1 requires dimerization with proteins. Specific in vivo association was observed between the bHLH and LIM proteins (LMO1 and LMO2). LYL1 readily forms heterodimeric complexes with E2A and may function as a dominant-negative preventing the activation of E2A responsive genes. LYL1 interacts also with p105 the precursor of NF-KappaB1 p50.
Homology The bHLH region of LYL1 and TAL1/SCL proteins show 82% amino acid identity, suggesting that these two proteins share at least some target genes and biologic functions. However, LYL-1 and TAL1diverge largely outside the bHLH region and display a distinct expression pattern in hematopoietic cells. Mouse Lyl-1 protein is 78% identical to human LYL1.

Implicated in

Note
  
Entity t(7;19)(q35;p13) --> TCRB/LYL1 in T-cell acute lymphoblastic leukemia, other T-ALL, acute myeloblastic leukemia (AML) or myelodysplastic syndrome (MDS)
Disease The LYL1 gene was originally identified at the chromosomal translocation t(7;19)(q35;p13) associated with T-ALL. However, over-expression of LYL1 has been reported in T-ALL cases without apparent chromosome aberration. Recent studies on leukemia cell lines and patient samples suggested its involvement in myeloid malignancies. Using real-time quantitative RT-PCR assay, the authors found that the expression of LYL1 was at a significantly higher level than normal bone marrow cells in the majority of cases of acute myeloblastic leukemia (AML) or myelodysplastic syndrome when compared to normal bone marrow. This study also showed that LYL1 was highly expressed in most AML cell lines and in CD34(+) AML cells.
Prognosis Expression of LYL1 is associated with unfavorable prognosis in T-ALL cases. LYL1(+) cases have a gene expression signature corresponding to that of the most immature normal T-cell precursors (CD4/CD8 double-negative cells), which express CD34 but not CD4, CD8, or CD3. Less favorable outcomes were observed in subgroups defined by gene expression profiles characteristic of TAL1(+) or LYL1(+) samples, which resemble late cortical and early pro-T thymocytes, respectively.
Cytogenetics The LYL1 gene was originally identified at the breakpoint of the translocation t(7;19)(q35;p13) in cases of T-ALL. It is the LYL1 gene but not protein that is structurally altered following t(7;19), resulting in its head-to-head juxtaposition with the T-cell antigen receptor beta gene (TCR-beta). The translocation resulted in truncation of the LYL1 gene and production of abnormal-sized RNAs, bringing LYL1 gene under the regulatory control of TCR-beta, and thus resulting in its ectopic expression. In addition to the t(7;19)(q35;p13), other translocations are t(1;19)(p34;p13), t(1;19)(p32;p13), t(9;19)(q34;p13), t(9;19)(q32;p13), t(10;19)(q24;p13), t(11;19)(p13;p13), t(15;19)(q22;p13) etc; it is not known if all of the translocations lead to enhanced expression of LYL1.
Hybrid/Mutated Gene The TCR-beta locus at 7q35 spans 685 kb (64-67 variable genes TRBV, 2 clusters of diversity, joining and constant segments).
Oncogenesis As discussed above, the LYL1 gene was first identified at t(7;19)(q35;p13) associated T-ALL. However, over-expression of LYL1 has been reported in T-ALL cases without apparent chromosome aberration. LYL1, TAL1 and TAL2 constitute a discrete subgroup of helix-loop-helix proteins, each of which can potentially contribute to the development of T-ALL. Specific in vivo association between the bHLH and LIM proteins is implicated in human T cell leukemia. LYL1 can readily form heterodimers with E2A and NF-KappaB1 p105 protein. It is possible that LYL1 may function as a dominant-negative preventing the activation of the tumor suppressors like E2A. Ectopic expression of LYL1 may also be involved in myeloid leukemia.
  

Bibliography

Age-related phenotypic and oncogenic differences in T-cell acute lymphoblastic leukemias may reflect thymic atrophy.
Asnafi V, Beldjord K, Libura M, Villarese P, Millien C, Ballerini P, Kuhlein E, Lafage-Pochitaloff M, Delabesse E, Bernard O, Macintyre E
Blood. 2004 ; 104 (13) : 4173-4180.
PMID 15054041
 
Muscarinic modulation of intrinsic burst firing in rat hippocampal neurons.
Azouz R, Jensen MS, Yaari Y
The European journal of neuroscience. 1994 ; 6 (6) : 961-966.
PMID 7952283
 
The SCL relative LYL-1 is required for fetal and adult hematopoietic stem cell function and B-cell differentiation.
Capron C, Lécluse Y, Kaushik AL, Foudi A, Lacout C, Sekkai D, Godin I, Albagli O, Poullion I, Svinartchouk F, Schanze E, Vainchenker W, Sablitzky F, Bennaceur-Griscelli A, Duménil D
Blood. 2006 ; 107 (12) : 4678-4686.
PMID 16514064
 
Prognostic importance of TLX1 (HOX11) oncogene expression in adults with T-cell acute lymphoblastic leukaemia.
Ferrando AA, Neuberg DS, Dodge RK, Paietta E, Larson RA, Wiernik PH, Rowe JM, Caligiuri MA, Bloomfield CD, Look AT
Lancet. 2004 ; 363 (9408) : 535-536.
PMID 14975618
 
Physical interaction of the bHLH LYL1 protein and NF-kappaB1 p105.
Ferrier R, Nougarede R, Doucet S, Kahn-Perles B, Imbert J, Mathieu-Mahul D
Oncogene. 1999 ; 18 (4) : 995-1005.
PMID 10023675
 
Structure, chromosome mapping, and expression of the mouse Lyl-1 gene.
Kuo SS, Mellentin JD, Copeland NG, Gilbert DJ, Jenkins NA, Cleary ML
Oncogene. 1991 ; 6 (6) : 961-968.
PMID 2067848
 
lyl-1, a novel gene altered by chromosomal translocation in T cell leukemia, codes for a protein with a helix-loop-helix DNA binding motif.
Mellentin JD, Smith SD, Cleary ML
Cell. 1989 ; 58 (1) : 77-83.
PMID 2752424
 
Oncogenic potential of the transcription factor LYL1 in acute myeloblastic leukemia.
Meng YS, Khoury H, Dick JE, Minden MD
Leukemia : official journal of the Leukemia Society of America, Leukemia Research Fund, U.K. 2005 ; 19 (11) : 1941-1947.
PMID 16094422
 
Specific in vivo association between the bHLH and LIM proteins implicated in human T cell leukemia.
Wadman I, Li J, Bash RO, Forster A, Osada H, Rabbitts TH, Baer R
The EMBO journal. 1994 ; 13 (20) : 4831-4839.
PMID 7957052
 

Citation

This paper should be referenced as such :
Minden, MD ; Meng, Y
LYL1 (lymphoblastic leukemia derived sequence 1)
Atlas Genet Cytogenet Oncol Haematol. 2007;11(2):99-101.
Free journal version : [ pdf ]   [ DOI ]
On line version : http://AtlasGeneticsOncology.org/Genes/LYL1ID51ch19p13.html


Other Leukemias implicated (Data extracted from papers in the Atlas) [ 4 ]
  t(1;7)(p36;p12) IKZF1/PRDM16
t(7;9)(q34;q32) TRB/TAL2
t(7;19)(q34;p13) TRB/LYL1
T-lineage acute lymphoblastic leukemia (T-ALL)


External links

Nomenclature
HGNC (Hugo)LYL1   6734
Cards
AtlasLYL1ID51ch19p13
Entrez_Gene (NCBI)LYL1  4066  lymphoblastic leukemia associated hematopoiesis regulator 1
AliasesbHLHa18
GeneCards (Weizmann)LYL1
Ensembl hg19 (Hinxton)ENSG00000104903 [Gene_View]  chr19:13209842-13213974 [Contig_View]  LYL1 [Vega]
Ensembl hg38 (Hinxton)ENSG00000104903 [Gene_View]  chr19:13209842-13213974 [Contig_View]  LYL1 [Vega]
ICGC DataPortalENSG00000104903
TCGA cBioPortalLYL1
AceView (NCBI)LYL1
Genatlas (Paris)LYL1
WikiGenes4066
SOURCE (Princeton)LYL1
Genetics Home Reference (NIH)LYL1
Genomic and cartography
GoldenPath hg19 (UCSC)LYL1  -     chr19:13209842-13213974 -  19p13.13   [Description]    (hg19-Feb_2009)
GoldenPath hg38 (UCSC)LYL1  -     19p13.13   [Description]    (hg38-Dec_2013)
EnsemblLYL1 - 19p13.13 [CytoView hg19]  LYL1 - 19p13.13 [CytoView hg38]
Mapping of homologs : NCBILYL1 [Mapview hg19]  LYL1 [Mapview hg38]
OMIM151440   
Gene and transcription
Genbank (Entrez)AI554151 AK311530 BC002796 BI908195 DB036722
RefSeq transcript (Entrez)NM_005583
RefSeq genomic (Entrez)NC_000019 NC_018930 NG_027756 NT_011295 NW_004929414
Consensus coding sequences : CCDS (NCBI)LYL1
Cluster EST : UnigeneHs.728534 [ NCBI ]
CGAP (NCI)Hs.728534
Alternative Splicing GalleryENSG00000104903
Gene ExpressionLYL1 [ NCBI-GEO ]   LYL1 [ EBI - ARRAY_EXPRESS ]   LYL1 [ SEEK ]   LYL1 [ MEM ]
Gene Expression Viewer (FireBrowse)LYL1 [ Firebrowse - Broad ]
SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
GenevisibleExpression in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)4066
GTEX Portal (Tissue expression)LYL1
Protein : pattern, domain, 3D structure
UniProt/SwissProtP12980   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
NextProtP12980  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProP12980
Splice isoforms : SwissVarP12980
PhosPhoSitePlusP12980
Domaine pattern : Prosite (Expaxy)BHLH (PS50888)   
Domains : Interpro (EBI)bHLH_dom   
Domain families : Pfam (Sanger)HLH (PF00010)   
Domain families : Pfam (NCBI)pfam00010   
Domain families : Smart (EMBL)HLH (SM00353)  
Conserved Domain (NCBI)LYL1
DMDM Disease mutations4066
Blocks (Seattle)LYL1
SuperfamilyP12980
Human Protein AtlasENSG00000104903
Peptide AtlasP12980
HPRD01046
IPIIPI00218258   IPI00979906   
Protein Interaction databases
DIP (DOE-UCLA)P12980
IntAct (EBI)P12980
FunCoupENSG00000104903
BioGRIDLYL1
STRING (EMBL)LYL1
ZODIACLYL1
Ontologies - Pathways
QuickGOP12980
Ontology : AmiGORNA polymerase II regulatory region sequence-specific DNA binding  RNA polymerase II transcription factor activity, sequence-specific DNA binding  blood vessel maturation  DNA binding  protein binding  nucleus  transcription, DNA-templated  regulation of transcription, DNA-templated  regulation of transcription from RNA polymerase II promoter  B cell differentiation  positive regulation of transcription, DNA-templated  protein dimerization activity  definitive hemopoiesis  
Ontology : EGO-EBIRNA polymerase II regulatory region sequence-specific DNA binding  RNA polymerase II transcription factor activity, sequence-specific DNA binding  blood vessel maturation  DNA binding  protein binding  nucleus  transcription, DNA-templated  regulation of transcription, DNA-templated  regulation of transcription from RNA polymerase II promoter  B cell differentiation  positive regulation of transcription, DNA-templated  protein dimerization activity  definitive hemopoiesis  
Pathways : KEGGTranscriptional misregulation in cancer   
NDEx NetworkLYL1
Atlas of Cancer Signalling NetworkLYL1
Wikipedia pathwaysLYL1
Orthology - Evolution
OrthoDB4066
GeneTree (enSembl)ENSG00000104903
Phylogenetic Trees/Animal Genes : TreeFamLYL1
HOVERGENP12980
HOGENOMP12980
Homologs : HomoloGeneLYL1
Homology/Alignments : Family Browser (UCSC)LYL1
Gene fusions - Rearrangements
Fusion : MitelmanTRB/LYL1 [-/19p13.2]  [t(7;19)(q34;p13)]  
Fusion : TICdbLYL1 [19p13.2]  -  TCR []
Polymorphisms : SNP and Copy number variants
NCBI Variation ViewerLYL1 [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)LYL1
dbVarLYL1
ClinVarLYL1
1000_GenomesLYL1 
Exome Variant ServerLYL1
ExAC (Exome Aggregation Consortium)LYL1 (select the gene name)
Genetic variants : HAPMAP4066
Genomic Variants (DGV)LYL1 [DGVbeta]
DECIPHER (Syndromes)19:13209842-13213974  ENSG00000104903
CONAN: Copy Number AnalysisLYL1 
Mutations
ICGC Data PortalLYL1 
TCGA Data PortalLYL1 
Broad Tumor PortalLYL1
OASIS PortalLYL1 [ Somatic mutations - Copy number]
Cancer Gene: CensusLYL1 
Somatic Mutations in Cancer : COSMICLYL1  [overview]  [genome browser]  [tissue]  [distribution]  
Mutations and Diseases : HGMDLYL1
LOVD (Leiden Open Variation Database)Whole genome datasets
LOVD (Leiden Open Variation Database)LOVD 3.0 shared installation
BioMutasearch LYL1
DgiDB (Drug Gene Interaction Database)LYL1
DoCM (Curated mutations)LYL1 (select the gene name)
CIViC (Clinical Interpretations of Variants in Cancer)LYL1 (select a term)
intoGenLYL1
NCG5 (London)LYL1
Cancer3DLYL1(select the gene name)
Impact of mutations[PolyPhen2] [SIFT Human Coding SNP] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
Diseases
OMIM151440   
Orphanet
MedgenLYL1
Genetic Testing Registry LYL1
NextProtP12980 [Medical]
TSGene4066
GENETestsLYL1
Huge Navigator LYL1 [HugePedia]
snp3D : Map Gene to Disease4066
BioCentury BCIQLYL1
ClinGenLYL1
Clinical trials, drugs, therapy
Chemical/Protein Interactions : CTD4066
Chemical/Pharm GKB GenePA30497
Clinical trialLYL1
Miscellaneous
canSAR (ICR)LYL1 (select the gene name)
Other databasehttp://www.cleanex.isb-sib.ch/cgi-bin/cleanex_query_result.pl?out_format=NICE&Entry_0=HGNC:6734
Probes
Litterature
PubMed25 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
CoreMineLYL1
EVEXLYL1
GoPubMedLYL1
iHOPLYL1
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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indexed on : Wed Apr 12 11:34:33 CEST 2017

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