Loss of TAL-1 protein activity induces premature apoptosis of Jurkat leukemic T cells upon medium depletion.

Abstract

Transcriptional activation of the tal‐1 gene occurs in ‐30% of patients with T cell Acute Lymphoblastic Leukemia and is therefore likely to be involved in human T cell leukemogenesis. However, the TAL‐1 protein functional properties involved in this process have not been assessed so far. We have derived a clonal subline of the Jurkat T cell line which produced solely a mutant truncated form of TAL‐1 protein. Sequencing of genomic DNA and cDNAs showed that the only transcribed tal‐1 allele of this mutant subline harbored a G nucleotide insertion at codon 270. The resulting frameshift modifies TAL‐1 residues 272‐278 and creates a stop at codon 279. Although the deletion of the 53 carboxy‐terminal residues of the TAL‐1 protein did not directly affect the TAL‐1 basic helix‐loop‐helix domain (residues 185‐243), it had drastic effects on TAL‐1 functional properties, since the mutant subline exhibited a dramatic decrease of protein binding activity to the TAL‐1 DNA consensus sequence. Growth curves indicated that the mutant subline exhibited premature apoptosis upon medium depletion or serum reduction when compared with the parental cells. However, no difference between Jurkat and the mutant subline was observed in etoposide‐ or Fas/APO‐1‐triggered apoptosis. Stable expression of the mutant TAL‐1 protein in Jurkat cells resulted in a phenotype that was similar to that of the mutant Jurkat subline, indicating that the TAL‐1 mutant protein behaved like a dominant negative mutant and that the premature apoptosis of the mutant subline upon medium depletion was the consequence of the loss of TAL‐1 protein activity.

Transcription of the SCL gene in erythroid and CD34 positive primitive myeloid cells is controlled by a complex network of lineage-restricted chromatin-dependent and chromatin-independent regulatory elements

“…Our results should be compared with those reported by Leroy-Viard et al, 1994 for the human SCL gene. This group described DNase I hypersensitive sites in human leukaemic T cell lines expressing SCL as a result of chromosome rearrangements and also in human erythroid cell lines (K562 and HEL).…”

Control of erythroid cell production via caspase-mediated cleavage of transcription factor SCL/Tal-1

“…3 SCL/Tal-1 has been reported to exert proliferative and antiapoptotic effects on hematopoietic cells and to function as a positive regulator of erythroid differentiation. [41][42][43][44] In the present study, we provide evidence that cleavage of SCL/Tal-1 by caspases is a key event in the negative regulation of erythropoiesis, being required for the amplification of caspase activation in erythroid progenitor cells. Comparative kinetic analysis of caspase-3, GATA-1 and SCL/Tal-1 in CD95-stimulated erythroblasts revealed that SCL/Tal-1 cleavage occurs during the early phase of death receptor signaling and is almost completed before downregulation of GATA-1 levels.…”

Cytokine response gene 8 (CR8) regulates the cell cycle G1-S phase transition and promotes cellular survival

“…For example, the Tal1 gene product, which is normally expressed in hematopoietic cells, and is also expressed abnormally in some cases of T cell acute lymphoblastic leukemia (T-ALL) as a result of chromosomal aberrations, protects IL-3-dependent 32D cells from cytokine-withdrawal-induced apoptosis (Condorelli et al, 1997). Loss of Tal1 has also been reported to result in increased sensitivty of Jurkat cells to serum-withdrawal-induced apoptosis (Leroy-Viard et al, 1995). Notably, two bHLH proteins, Dermo1 and twist, were identi®ed in a screen for genes which could protect from serum-withdrawal and c-myc overexpression-induced apoptosis of Rat1 ®broblasts (Maestro et al, 1999).…”