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

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)

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.

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.

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.

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.

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

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).