SCL and LMOI alter thymocyte differentiation: inhibition of E2A-HEB function and pre-T alpha chain expression

Cooperation between the stem cell leukemia (SCL) transcription factor and i ts nuclear partners LMO1 or LMO2 induces aggressive T cell acute lymphoblas tic leukemia when inappropriately expressed in T cells. This study examined the cellular and molecular targets of the SCL-LMO complex at the preleukem ic stage. We show that SCL and its partners are coexpressed in the most pri mitive thymocytes. Maturation to the pre-T cell stage is associated with a down-regulation of SCL and LMO1 and LMO2, and a concomitant up-regulation o f E2A and HEB expression. Moreover, enforced expression of SCL-LMO1 inhibit s T cell differentiation and recapitulates a loss of HEB function, causing a deregulation of the transition checkpoint from the CD4(-)CD8(-) to CD4(+) CD8(+) stages. Finally, we identify the gene encoding pT alpha as a downstr eam target of HEB that is specifically repressed by the SCL-LMO complex.