Ectopic TAL-1/SCL expression in phenotypically normal or leukemic myeloid precursors: Proliferative and antiapoptotic effects coupled with a differentiation blockade

The TAL-I gene specifies a basic helix-loop-helix domain (bHLH) transcription factor, which heterodimerizes with E2A gene family proteins, tal-l protein is abnormally expressed in the majority of T-cell acute lymphoblastic leukemias (T-ALLs), tal-l is expressed and plays a significant role in normal erythropoietic differentiation and maturation, while its expression in early myeloid differentiation is abruptly shut off at the level of late progenitors/early differentiated precursors (G. L. Condorelli, L. Vitelli, M. Valtieri, I. Marta, E. Montesoro, V. Lulli, R. Baer, and C. Peschle, Blood 86:164-175, 1995). We show that in late myeloid progenitors (the phenotypically normal murine 32D cell line) and early leukemic precursors (the human HL-60 promyelocytic leukemia cell line) ectopic tal-l expression induces (i) a proliferative effect under suboptimal culture conditions (i,e., low growth factor and serum concentrations respectively), via an antiapoptotic effect in 32D cells or increased DNA synthesis in HL-60 cells, and (ii) a total or marked inhibitory effect on differentiation, respectively, on granulocyte 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 temperature does not exert a proliferative effect but causes p53-mediated apoptosis, i.e., the tal-l proliferative effect depends on the integrity of the cell cycle checkpoints of the host cell, as observed for c-myc and other oncogenes, tal-l mutant experiments indicate that ectopic tal-l effects are mediated by both the DNA-binding and the heterodimerization domains, while the N-terminally truncated tal-l variant (M3) expressed in T-ALL malignant cells mimics the effects of the wild-type protein, Altogether, our results (i) indicate proliferative and antidifferentiative effects of ectopic tal-l expression, (ii) shed light on the underlying mechanisms (i.e., requirement for the integrity of the tal-l bHLH domain and cell cycle checkpoints in the host cell, particularly p53, and (iii) provide new experimental models to further investigate these mechanisms.