The DNA binding activity of TAL-1 is not required to induce leukemia/lymphoma in mice.
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).
O'Neil
J
J
University of Massachusetts Medical School, Department of Molecular Genetics and Microbiology and the Cancer Center, 373 Plantation Street, Worcester, Massachusetts, MA 01605, USA.
Billa
M
M
Oikemus
S
S
Kelliher
M
M
D048868:Adaptor Proteins, Signal Transducing; D017502:Adenovirus E2 Proteins / Q000378:metabolism; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins; D015704:CD4 Antigens / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology; D047390:Casein Kinase II; D002454:Cell Differentiation; D004247:DNA / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000378:metabolism*; D019281:Dimerization; D004195:Disease Models, Animal; D018257:Helix-Loop-Helix Motifs; D006801:Humans; D060588:LIM Domain Proteins; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000378:metabolism*; D008223:Lymphoma; D008667:Metalloproteins / Q000096:biosynthesis; D051379:Mice; D008822:Mice, Transgenic; D016296:Mutagenesis; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D000073942:T-Cell Acute Lymphocytic Leukemia Protein 1; D051820:TCF Transcription Factors; D013945:Thymoma / Q000276:immunology; D013950:Thymus Gland / Q000166:cytology; D013953:Thymus Neoplasms / Q000276:immunology; D058125:Transcription Factor 7-Like 1 Protein; D014157:Transcription Factors / Q000378:metabolism*
D048868:Adaptor Proteins, Signal Transducing; D017502:Adenovirus E2 Proteins; D051792:Basic Helix-Loop-Helix Proteins; D015704:CD4 Antigens; D047390:Casein Kinase II; D004247:DNA; D004268:DNA-Binding Proteins; D060588:LIM Domain Proteins; D008667:Metalloproteins; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D000073942:T-Cell Acute Lymphocytic Leukemia Protein 1; D051820:TCF Transcription Factors; D058125:Transcription Factor 7-Like 1 Protein; D014157:Transcription Factors; C085117:LMO2 protein, human; C513188:Lmo2 protein, mouse; C544912:TCF7L1 protein, human; C489366:Tal1 protein, mouse; C544913:Tcf7l1 protein, mouse; C067143:TAL1 protein, human