LYL1 (lymphoblastic leukemia derived sequence 1)

2006-12-01   Yuesheng Meng  , Mark D. Minden  

Department of Cellular and Molecular Biology, Ontario Cancer Institute\\\/Princess Margaret Hospital, University Health Network, Toronto, Canada

Identity

HGNC
LYL1
LOCATION
19p13.2
LOCUSID
4066
ALIAS
bHLHa18
FUSION GENES
Show Gene Fusions

DNA/RNA

Note

DNA size: 3.83 kb; mRNA size: 1492 bp; Exons: 4.
Atlas Image

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.

Proteins

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

Entity name
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 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.

Article Bibliography

Pubmed IDLast YearTitleAuthors
150540412004Age-related phenotypic and oncogenic differences in T-cell acute lymphoblastic leukemias may reflect thymic atrophy.Asnafi V et al
79522831994Muscarinic modulation of intrinsic burst firing in rat hippocampal neurons.Azouz R et al
165140642006The SCL relative LYL-1 is required for fetal and adult hematopoietic stem cell function and B-cell differentiation.Capron C et al
149756182004Prognostic importance of TLX1 (HOX11) oncogene expression in adults with T-cell acute lymphoblastic leukaemia.Ferrando AA et al
100236751999Physical interaction of the bHLH LYL1 protein and NF-kappaB1 p105.Ferrier R et al
20678481991Structure, chromosome mapping, and expression of the mouse Lyl-1 gene.Kuo SS et al
27524241989lyl-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 et al
160944222005Oncogenic potential of the transcription factor LYL1 in acute myeloblastic leukemia.Meng YS et al
79570521994Specific in vivo association between the bHLH and LIM proteins implicated in human T cell leukemia.Wadman I et al

Other Information

Locus ID:

NCBI: 4066
MIM: 151440
HGNC: 6734
Ensembl: ENSG00000104903

Variants:

dbSNP: 4066
ClinVar: 4066
TCGA: ENSG00000104903
COSMIC: LYL1

RNA/Proteins

Gene IDTranscript IDUniprot
ENSG00000104903ENST00000264824P12980
ENSG00000104903ENST00000590974K7ER61

Expression (GTEx)

0
50
100
150
Adipose - Subcutaneous
Adipose - Visceral
Adrenal Gland
Artery - Aorta
Artery - Tibial
Bladder
Brain - Amygdala
Brain - Anterior cingulate cortex
Brain - Caudate
Brain - Cerebellar Hemisphere
Brain - Cerebellum
Brain - Cortex
Brain - Frontal Cortex
Brain - Hippocampus
Brain - Hypothalamus
Brain - Nucleus accumbens
Brain - Putamen
Brain - Spinal cord
Brain - Substantia nigra
Breast - Mammary Tissue
Cells - Cultured fibroblasts
Cells - EBV - transformed lymphocytes
Cervix - Ectocervix
Cervix - Endocervix
Colon - Sigmoid
Colon - Transverse
Esophagus - Gastroesophageal Junction
Esophagus - Mucosa
Esophagus - Muscularis
Fallopian Tube
Heart - Atrial Appendage
Heart - Left Ventricle
Kidney - Cortex
Kidney - Medulla
Liver
Lung
Minor Salivary Gland
Muscle - Skeletal
Nerve - Tibial
Ovary
Pancreas
Pituitary
Prostate
Skin - Not Sun Exposed
Skin - Sun Exposed
Small Intestine - Terminal Ileum
Spleen
Stomach
Testis
Thyroid
Uterus
Vagina
Whole Blood

Pathways

PathwaySourceExternal ID
Transcriptional misregulation in cancerKEGGko05202
Transcriptional misregulation in cancerKEGGhsa05202

References

Pubmed IDYearTitleCitations
358427032022Super-enhancer profiling identifies novel critical and targetable cancer survival gene LYL1 in pediatric acute myeloid leukemia.6
362154772022LYL1 facilitates AETFC assembly and gene activation by recruiting CARM1 in t(8;21) AML.2
358427032022Super-enhancer profiling identifies novel critical and targetable cancer survival gene LYL1 in pediatric acute myeloid leukemia.6
362154772022LYL1 facilitates AETFC assembly and gene activation by recruiting CARM1 in t(8;21) AML.2
307557072019Destabilization of AETFC through C/EBPα-mediated repression of LYL1 contributes to t(8;21) leukemic cell differentiation.3
307557072019Destabilization of AETFC through C/EBPα-mediated repression of LYL1 contributes to t(8;21) leukemic cell differentiation.3
297165492018LYL1 gene amplification predicts poor survival of patients with uterine corpus endometrial carcinoma: analysis of the Cancer genome atlas data.6
297165492018LYL1 gene amplification predicts poor survival of patients with uterine corpus endometrial carcinoma: analysis of the Cancer genome atlas data.6
233279222013Activity of a heptad of transcription factors is associated with stem cell programs and clinical outcome in acute myeloid leukemia.43
238125882013A stable transcription factor complex nucleated by oligomeric AML1-ETO controls leukaemogenesis.79
233279222013Activity of a heptad of transcription factors is associated with stem cell programs and clinical outcome in acute myeloid leukemia.43
238125882013A stable transcription factor complex nucleated by oligomeric AML1-ETO controls leukaemogenesis.79
196082732010Multiple mechanisms induce ectopic expression of LYL1 in subsets of T-ALL cell lines.11
204182842010LYL1 activity is required for the maturation of newly formed blood vessels in adulthood.10
208447612010LYL1 degradation by the proteasome is directed by a N-terminal PEST rich site in a phosphorylation-independent manner.4

Citation

Yuesheng Meng ; Mark D. Minden

LYL1 (lymphoblastic leukemia derived sequence 1)

Atlas Genet Cytogenet Oncol Haematol. 2006-12-01

Online version: http://atlasgeneticsoncology.org/gene/51/lyl1