Tal-1 induces T cell acute lymphoblastic leukemia accelerated by casein kinase IIalpha.
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.
Department of Genetics, Harvard Medical School, Howard Hughes Medical Institute, Boston, MA 02115, USA.
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Kelliher
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Seldin
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Leder
D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins; D047390:Casein Kinase II; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D004195:Disease Models, Animal; D006801:Humans; D016130:Immunophenotyping; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000209:etiology* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D009857:Oncogenes / Q000235:genetics; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000502:physiology*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D012333:RNA, Messenger / Q000032:analysis; D012334:RNA, Neoplasm / Q000032:analysis; D000073942:T-Cell Acute Lymphocytic Leukemia Protein 1; D013945:Thymoma / Q000737:chemistry / Q000209:etiology / Q000473:pathology; D013950:Thymus Gland / Q000737:chemistry; D013953:Thymus Neoplasms / Q000737:chemistry / Q000209:etiology* / Q000473:pathology; D014157:Transcription Factors; D019076:Transgenes / Q000235:genetics
D051792:Basic Helix-Loop-Helix Proteins; D047390:Casein Kinase II; D004268:DNA-Binding Proteins; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D000073942:T-Cell Acute Lymphocytic Leukemia Protein 1; D014157:Transcription Factors; C489366:Tal1 protein, mouse; C067143:TAL1 protein, human