casein-kinase-ii and Leukemia-Lymphoma--Adult-T-Cell

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 lymphoblastic leukemia (T-ALL). Similarly, mis-expression of tal-1 in the thymus of transgenic mice results in the development of clonal T cell lymphoblastic leukemia. To determine the mechanism(s) of tal-1-induced leukemogenesis, we created transgenic mice expressing a DNA binding mutant of tal-1. Surprisingly, these mice develop disease, demonstrating that the DNA binding properties 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 CD8-single positive thymocytes but inhibits the development of CD4-single positive cells: effects also observed in E2A-deficient mice. Our study suggests that the bHLH protein tal-1 contributes to leukemia by interfering with E2A protein function(s).

Topics: Adaptor Proteins, Signal Transducing; Adenovirus E2 Proteins; Animals; Basic Helix-Loop-Helix Transcription Factors; Casein Kinase II; CD4 Antigens; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Cell Differentiation; Dimerization; Disease Models, Animal; DNA; DNA-Binding Proteins; Helix-Loop-Helix Motifs; Humans; Leukemia-Lymphoma, Adult T-Cell; LIM Domain Proteins; Lymphoma; Metalloproteins; Mice; Mice, Transgenic; Mutagenesis; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins; T-Cell Acute Lymphocytic Leukemia Protein 1; TCF Transcription Factors; Thymoma; Thymus Gland; Thymus Neoplasms; Transcription Factor 7-Like 1 Protein; Transcription Factors

A 2985 bp cDNA was isolated from a Lambda Zap Express library and sequenced. The cDNA appeared to represent a previously unknown gene that encodes and acidic 757 amino acid protein containing a bromodomain, several potential sites for phosphorylation by casein kinase-II and small proline-rich segments. The results suggest that the encoded protein might be a novel transcription factor.

Topics: Amino Acid Sequence; Base Sequence; Casein Kinase II; Cloning, Molecular; DNA, Complementary; Gene Library; Genes; Humans; Leukemia-Lymphoma, Adult T-Cell; Molecular Sequence Data; Phosphorylation; Protein Processing, Post-Translational; Protein Serine-Threonine Kinases; Protein Structure, Tertiary; Receptors, Thyroid Hormone; Sequence Alignment; Sequence Homology, Amino Acid; Transcription Factors; Tumor Cells, Cultured

Ectopic activation of the TAL-1 gene in T lymphocytes occurs in the majority of cases of human T cell acute lymphoblastic leukemia (T-ALL), yet experiments to date have failed to demonstrate a direct transforming capability for tal-1. The tal-1 gene product is a serine phosphoprotein and basic helix-loop-helix (bHLH) transcription factor known to regulate embryonic hematopoiesis. We have established a transgenic mouse model in which tal-1 mis-expression in the thymus results in the development of clonal T cell lymphoblastic leukemia/lymphoma. Thus, overexpression of tal-1 alone can be transforming, verifying its pathogenic role in human T-ALL. In addition, leukemogenesis is accelerated dramatically by transgenic co-expression of tal-1 and the catalytic subunit of casein kinase IIalpha (CKIIalpha), a serine/threonine protein kinase known to modulate the activity of other bHLH transcription factors. Although tal-1 is a substrate for CKII, the synergy of the tal-1 and CKIIalpha transgenes appears to be indirect, perhaps mediated through the E protein heterodimeric partners of tal-1. These studies prove that dysregulated tal-1 is oncogenic, providing a direct molecular explanation for the malignancies associated with TAL-1 activation in human T-ALL.

Topics: Animals; Basic Helix-Loop-Helix Transcription Factors; Casein Kinase II; Disease Models, Animal; DNA-Binding Proteins; Humans; Immunophenotyping; Leukemia-Lymphoma, Adult T-Cell; Mice; Mice, Transgenic; Oncogenes; Phosphorylation; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins; RNA, Messenger; RNA, Neoplasm; T-Cell Acute Lymphocytic Leukemia Protein 1; Thymoma; Thymus Gland; Thymus Neoplasms; Transcription Factors; Transgenes