Tal-1 induces T cell acute lymphoblastic leukemia accelerated by casein kinase IIalpha

EMBO J. 1996 Oct 1;15(19):5160-6.

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

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Basic Helix-Loop-Helix Transcription Factors
  • Casein Kinase II
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism
  • DNA-Binding Proteins / physiology*
  • Disease Models, Animal
  • Humans
  • Immunophenotyping
  • Leukemia-Lymphoma, Adult T-Cell / etiology*
  • Leukemia-Lymphoma, Adult T-Cell / pathology
  • Mice
  • Mice, Transgenic
  • Oncogenes / genetics
  • Phosphorylation
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / physiology*
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins / physiology*
  • RNA, Messenger / analysis
  • RNA, Neoplasm / analysis
  • T-Cell Acute Lymphocytic Leukemia Protein 1
  • Thymoma / chemistry
  • Thymoma / etiology
  • Thymoma / pathology
  • Thymus Gland / chemistry
  • Thymus Neoplasms / chemistry
  • Thymus Neoplasms / etiology*
  • Thymus Neoplasms / pathology
  • Transcription Factors*
  • Transgenes / genetics

Substances

  • Basic Helix-Loop-Helix Transcription Factors
  • DNA-Binding Proteins
  • Proto-Oncogene Proteins
  • RNA, Messenger
  • RNA, Neoplasm
  • T-Cell Acute Lymphocytic Leukemia Protein 1
  • Tal1 protein, mouse
  • Transcription Factors
  • TAL1 protein, human
  • Casein Kinase II
  • Protein-Serine-Threonine Kinases