Formation of in vivo complexes between the TAL1 and E2A polypeptides of leukemic T cells.

Abstract

Tumor-specific activation of the TALI gene occurs in "r.25% of patients with T-cell acute lymphoblastic leukemia (T-ALL). The TALI gene products possess a basic helix-oop-belix (bHLH) domain that interacts in vitro with the bHLH proteins (E12 and E47) encoded by the E2A locus. We have now applied two independent methods, the two-hybrid procedure and co-immunoprecipitation analysis, to demonstrate that TALl and E2A polypeptides also associate in vivo.These studies show that the bHLH domain of TALl selectively interacts with the bHLH domains of E12 and E47, but not with the Idl helix-oop-helix protein. TALl does not self-asiate to form homodimeric complexes, implying that the in vivo functions of TALl depend on heterologous interaction with other bHLH proteins such as E12 and E47. Co-immunoprecipitation analysis revealed the presence of endogenous TAL1/E2A complexes in Jurkat cells, a leukemic line derived from a T-ALL patient. Thus, the malignant properties ofTALl may be due to obligate interaction with the E2A polypeptides.

Overexpression of a transcription factor LYL1 induces T- and B-cell lymphoma in mice

“…In T-lymphocytes, E2A interacts with HEB, a member of the Class I bHLH family and activates target genes, whereas in Blymphocytes, E2A functions through the formation of a homodimer to regulate downstream genes (Lazorchak et al, 2005;Murre, 2005). As LYL1 can also interact with E2A (Hsu et al, 1994;Xia et al, 1994;Miyamoto et al, 1996), we asked whether ectopic overexpression of LYL1 had any effect on E2A dimerization. By using a mammalian two-hybrid system, we found that LYL1 interacted with E2A although this interaction was weaker than that of E2A-HEB ( Figure 4a).…”

“…Similar to LYL1, sustained expression of TAL1/2 owing to chromosomal translocation is associated with a T-cell leukemia/lymphoma (Xia et al, 1991;Begley and Green, 1999). Both LYL1 and TAL1/2 proteins can interact with Class I bHLH proteins (Hsu et al, 1994;Xia et al, 1994;Miyamoto et al, 1996) and LIM-domain-only (LMO) proteins through their bHLH motifs.…”

The DNA binding activity of TAL-1 is not required to induce leukemia/lymphoma in mice

“…Thus, heterodimer formation is essential for the DNA-binding activity and functional properties of these proteins. A stable tal-1/E2A complex has been detected in Jurkat cells (Hsu et al, 1994b). However, it remains unclear whether this complex is a consistent feature associated with tal-1-induced leukemia.…”

“…In human leukemic Jurkat cells, tal-1 does not homodimerize, but forms stable heterodimers with the ubiquitously expressed bHLH E2A proteins, E12 and E47 (Hsu et al, 1994b). Members of the E2A family include E2-2, HEB and the products of the E2A gene E47 and E12 (Murre et al, 1989;Henthorn et al, 1990;Hu et al, 1992).…”

p300 functions as a transcriptional coactivator for the TAL1/SCL oncoprotein

“…In addition to a full-length protein (pp47 TAL1 ), which has been detected in essentially all cells that transcribe the gene (Cheng et al, 1993;Hsu et al, 1994b), an amino-terminally truncated protein (pp24 TAL1 ) generated through alternative splicing has been observed in human and murine leukemia cell lines (Cheng et al, 1993;Hsu et al, 1994b) and Friend virus-induced proerythroblasts (Prasad et al, 1995). This shorter isoform is also the sole TAL1 species expressed in leukemias with the rare SIL-TAL1 d 3 deletion (Bash et al, 1993).…”