t(7;19)(q34;p13) TRB/LYL1

2003-01-01   Jacques Boyer  

1.Laboratoire d hématologie, CH du MANS, France

Clinics and Pathology

Disease

Specifically associated with T-cell Acute lymphoblastic leukemia (T-ALL)

Phenotype stem cell origin

Recents works, using oligonucleotide microarrays, show that several gene expression signatures are indicative of leukemic arrest at specific stages of normal thymocyte development :
  • LYL1 signature : pro-T (CD34+ CD3- CD4- CD8- CD1a-)
  • HOX11 : early cortical thymocyte and TAL1 late cortical thymocyte.
  • LYL1 positivity is related to higher expression levels of the MYCN, LMO2 and PLZF proto-oncogenes as well as the antiapoptotic gene BCL2.These findings have clinical importance (see Prognosis)

    • Epidemiology

    Rare : < 1% among T-ALL. The t(7;9)(q34;q32) is present in one case of a serie of 5 patients with 7q34 involvment.

    Prognosis

    HOX11 activation is significantly associated with a favorable prognosis, while expression of TAL1, LYL1 and surprisingly HOX11L2 confers a much worse response to treatment.The upregulation of BCL2 may explain their relative resistance to chemotherapy.

    Genes Involved and Proteins

    Gene name
    TRB (T cell Receptor Beta)
    Location
    7q34
    Dna rna description
    The TRB locus at 7q35 spans 685 Kb. The locus contains 2 types of coding elements : TCR elements (64-67 variable genes TRBV, 2 clusters of diversity, joining and constant segments) and 8 trypsinogen genes.
    Protein description
    T cell receptor beta chains.
    Gene name
    LYL1 (lymphoblastic leukemia derived sequence 1)
    Location
    19p13.2
    Note
    The LYL1 gene is assigned to 19p13.2-p13.1 by fluorescence in situ hybridation.
    Dna rna description
    An RNA of about 1.5 kb is transcribed from this gene in a wide variety of lymphoid cell lines with the notable exception of thymocytes and T cells.
    Protein description
    LYL1 encodes a basic helix-loop-helix (bHLH) phosphoprotein (size 108 amino acids) that is highly. Related to TAL1 : TAL1 and LYL1 HLH proteins show an 87% level of aminoacid identity.

    Result of the Chromosomal Anomaly

    Description

    The LYL1 gene is structurally altered following the t(7;19) translocation, resulting in its head-to-head juxtaposition with the T cell receptor beta gene.In the human T cell line SUP-T7 established from an acute lymphoblastic leukemia, nucleotide sequence analysis showed that the point of crossover on chromosome 7 occured immediately adjacent to joining segment beta 1.1 within the TCR beta gene, suggesting that this translocation resulted from an error in TCR gene rearrangement.The t(7;19) resulted in truncation of the LYL1 gene and production of abnormal-sized RNAs suggesting a role for LYL1 in the pathogenesis of T Leukemia.

    Oncogenesis

    Several helix-loop-helix (HLH) proteins are proposed to function as transcriptionnal regulatory factors based on their ability to bind in vitro the E-box motif of transcriptional enhancers. The enhancer binding HLH proteins include E47 and E12, two distinct but related polypeptides encoded by E2A gene that are able to form heterologous complexes with other HLH proteins like TAL1 and LYL1 polypeptides.
    Thus LYL1 may function as a dominant-negative mutant preventing the activation of E2A responsive genes. It is plausible that the inactivation of E2A target genes is an essential and common step toward the development of a number of T-cell malignancies.
    LYL1 interacts also with p105 the precursor of NF-KappaB1 p50. Biochemical studies indicate that this interaction is mediated by the HLH motif of LYL1 and the ankyrin-like motifs of p105.
    Ectopic expression of LYL1 cause a significant decrease in NF-KappaB- dependant transcription associated with a reduced level of NF-KappaB-dependant proteins.

    Article Bibliography

    Pubmed IDLast YearTitleAuthors
    86053271996Cytogenetic abnormalities in adult acute lymphoblastic leukemia: correlations with hematologic findings outcome. A Collaborative Study of the Group Français de Cytogénétique Hématologique.
    81426191993TAL1, TAL2 and LYL1: a family of basic helix-loop-helix proteins implicated in T cell acute leukaemia.Baer R et al
    92347341997E2A deficiency leads to abnormalities in alphabeta T-cell development and to rapid development of T-cell lymphomas.Bain G et al
    120868902002Gene expression signatures define novel oncogenic pathways in T cell acute lymphoblastic leukemia.Ferrando AA et al
    100236751999Physical interaction of the bHLH LYL1 protein and NF-kappaB1 p105.Ferrier R 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
    86283071996Helix-loop-helix proteins LYL1 and E2a form heterodimeric complexes with distinctive DNA-binding properties in hematolymphoid cells.Miyamoto A et al
    13770081992Karyotype and T-cell receptor expression in T-lineage acute lymphoblastic leukemia.Secker-Walker LM et al
    29626501988Clinical and biologic characterization of T-cell neoplasias with rearrangements of chromosome 7 band q34.Smith SD et al
    84325251993Fluorescence in situ hybridization mapping of human chromosome 19: cytogenetic band location of 540 cosmids and 70 genes or DNA markers.Trask B et al

    Summary

    Fusion gene

    TRB/LYL1 TRB (-) LYL1 (19p13.2) M t(7;19)(q34;p13)

    Note

    Non random translocations involving the short arm of chromosome 19 are observed in acute leukemia. The 19p13 genes E2A and LYL1 (see below) lie at two different translocation breakpoints in acute lymphoblastic leukemia.For instance the E2A gene is involved in the t(1;19)(q23 ;p13) in acute pre-B leukemia (B-ALL) and the LYL1 gene is structurally altered in the t(7;19)(q34 ;p13) in T cell leukemia (T-ALL).

    Citation

    Jacques Boyer

    t(7;19)(q34;p13) TRB/LYL1

    Atlas Genet Cytogenet Oncol Haematol. 2003-01-01

    Online version: http://atlasgeneticsoncology.org/haematological/1060/t(7;19)(q34;p13)-trb-lyl1