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

Activation of the basic helix-loop-helix (bHLH) gene TAL-1 (or SCL) is the most frequent gain-of-function mutation in pediatric T cell acute lymphobla stic leukemia (T-ALL), Similarly, mis-expression of tal-1 in the thymus of transgenic mice results in the development of clonal T cell lymphoblastic l eukemia. To determine the mechanism(s) of tal-1-induced leukemogenesis, we created transgenic mice expressing a DNA binding mutant of tal-1, Surprisin gly, these mice develop disease, demonstrating that the DNA binding propert ies of tal-1 are not required to induce leukemia/lymphoma in mice. However, wild type tal-1 and the DNA binding mutant both form stable complexes with E2A proteins. In addition, tal-1 stimulates differentiation of CDS-single positive thymocytes but inhibits the development of CD4-single positive cel ls: effects also observed in E2A-deficient mice. Our study suggests that th e bHLH protein tal-1 contributes to leukemia by interfering with E2A protei n function(s).