ECTOPIC TAL-1 SCL EXPRESSION IN PHENOTYPICALLY NORMAL OR LEUKEMIC MYELOID PRECURSORS - PROLIFERATIVE AND ANTIAPOPTOTIC EFFECTS COUPLED WITHA DIFFERENTIATION BLOCKADE/

The TAL-I gene specifies a basic helix-loop-helix domain (bHLH) transc ription factor, which heterodimerizes with E2A gene family proteins, t al-l protein is abnormally expressed in the majority of T-cell acute l ymphoblastic leukemias (T-ALLs), tal-l is expressed and plays a signif icant role in normal erythropoietic differentiation and maturation, wh ile its expression in early myeloid differentiation is abruptly shut o ff at the level of late progenitors/early differentiated precursors (G . L. Condorelli, L. Vitelli, M. Valtieri, I. Marta, E. Montesoro, V. L ulli, R. Baer, and C. Peschle, Blood 86:164-175, 1995). We show that i n late myeloid progenitors (the phenotypically normal murine 32D cell line) and early leukemic precursors (the human HL-60 promyelocytic leu kemia cell line) ectopic tal-l expression induces (i) a proliferative effect under suboptimal culture conditions (i,e., low growth factor an d serum concentrations respectively), via an antiapoptotic effect in 3 2D cells or increased DNA synthesis in HL-60 cells, and (ii) a total o r marked inhibitory effect on differentiation, respectively, on granul ocyte colony-stimulating factor-induced granulopoiesis in 32D cells or retinoic acid- and vitamin D3-induced granulo- and monocytopoiesis in HL-60 cells, Furthermore, experiments with 32D temperature-sensitive p53 cells indicate that aberrant tal-l expression at the permissive te mperature does not exert a proliferative effect but causes p53-mediate d apoptosis, i.e., the tal-l proliferative effect depends on the integ rity of the cell cycle checkpoints of the host cell, as observed for c -myc and other oncogenes, tal-l mutant experiments indicate that ectop ic tal-l effects are mediated by both the DNA-binding and the heterodi merization domains, while the N-terminally truncated tal-l variant (M3 ) expressed in T-ALL malignant cells mimics the effects of the wild-ty pe protein, Altogether, our results (i) indicate proliferative and ant idifferentiative effects of ectopic tal-l expression, (ii) shed light on the underlying mechanisms (i.e., requirement for the integrity of t he tal-l bHLH domain and cell cycle checkpoints in the host cell, part icularly p53, and (iii) provide new experimental models to further inv estigate these mechanisms.