Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Basic Helix-Loop-Helix Transcription Factors
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Casein Kinase II
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism
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DNA-Binding Proteins / physiology*
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Disease Models, Animal
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Humans
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Immunophenotyping
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Leukemia-Lymphoma, Adult T-Cell / etiology*
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Leukemia-Lymphoma, Adult T-Cell / pathology
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Mice
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Mice, Transgenic
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Oncogenes / genetics
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Phosphorylation
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Protein Serine-Threonine Kinases / genetics
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Protein Serine-Threonine Kinases / physiology*
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins / metabolism
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Proto-Oncogene Proteins / physiology*
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RNA, Messenger / analysis
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RNA, Neoplasm / analysis
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T-Cell Acute Lymphocytic Leukemia Protein 1
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Thymoma / chemistry
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Thymoma / etiology
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Thymoma / pathology
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Thymus Gland / chemistry
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Thymus Neoplasms / chemistry
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Thymus Neoplasms / etiology*
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Thymus Neoplasms / pathology
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Transcription Factors*
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Transgenes / genetics
Substances
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Basic Helix-Loop-Helix Transcription Factors
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DNA-Binding Proteins
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Proto-Oncogene Proteins
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RNA, Messenger
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RNA, Neoplasm
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T-Cell Acute Lymphocytic Leukemia Protein 1
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Tal1 protein, mouse
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Transcription Factors
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TAL1 protein, human
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Casein Kinase II
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Protein Serine-Threonine Kinases