Helix-loop-helix (E2-5, HEB, TAL1 and Id1) protein interaction with the TCRαδ enhancers.

In order to dissect the correlation between aberrant TAL1 basic-helix-loop-helix (b-HLH) expression and the exclusive development of T cell acute lymphoblastic leukemias (T-ALL) of the TCRαβ lineage, we have assessed the ability of class A b-HLH proteins to regulate the TCRα and δ enhancers. We demonstrate that E47S binds to TCRα but not to TCRδ E-boxes in vitro. Despite this, neither E2-5 nor HEB transactivate the TCRα enhancer in NIH 3T3, nor did Id1 modify endogenously driven TCRα [αE1-4] activity in a TCRαβ cell line. We also demonstrate that TAL-1 inhibits both binding of E47S to αE3 and αE4 and endogenous transactivation of the TCRα enhancer. Comparison of the activity of the minimal [αE1-2] fragment, which contains no E-boxes, with the accessory [αE3-4] fragment, which contains two, suggested some contribution from the latter to TCRα enhancer activity in HPB-ALL. TCR [αE1-2] activity was partially (40%) inhibited by TAL1 but not all by Id1. In contrast, [αE3-4] activity was almost completely inhibited by TAL1 (80%) and slightly reduced by Id1 (15%). These data demonstrate that class A b-HLH regulation of the TCRα enhancer E-boxes differs from their B lymphoid Igμ counterparts and suggest a novel mechanism on transcriptional inhibition by TAL1, which may be, at least partly, independent of E-box-mediated activation, as we currently recognize it. They also clearly demonstrate that the restriction of TAL1 deregulation to T-ALL of the TCRαβ lineage is not due to induction of TCRα enhancer activity by the TAL1 protein. [ABSTRACT FROM PUBLISHER]