NF-kappaB activation in premalignant mouse tal-1/scl thymocytes and tumors.
TAL-1/SCL activation is a common genetic event in pediatric T-cell acute lymphoblastic leukemia (T-ALL). Expression of tal-1/scl or a DNA binding mutant of tal-1/scl induces arrest of thymocyte development, resulting in decreases in double-positive and single-positive CD4 thymocytes. Moreover, nuclear p65/p50 heterodimers are detected in premalignant tal-1/scl and mut tal-1/scl thymocytes, suggesting that E2A depletion may induce developmental arrest and stimulate NF-kappaB activation. Increased NF-kappaB activity is also observed in tal-1/scl tumors and bcl-2 is overexpressed. To examine the contribution of NF-kappaB to tal-1/scl tumor growth in vivo, we expressed a mutant form of IkappaBalpha in tal-1/scl tumor cells. Although expression of mutant IkappaBalpha inhibited the tumor necrosis factor alpha (TNF-alpha)-induced NF-kappaB response, it had no effect on tumor growth in mice. These data suggest that NF-kappaB activation is an early event in tal-1/scl-induced leukemogenesis, associated with arrest of thymocyte development, and does not appear to contribute to tal-1/scl-induced tumor growth.
O'Neil
Jennifer
J
Department of Cancer Biology, University of Massachusetts Medical School, Worcester, USA.
Ventura
Juan-Jose
JJ
Cusson
Nicole
N
Kelliher
Michelle
M
D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins; D015704:CD4 Antigens / Q000032:analysis; D016827:CD8 Antigens / Q000032:analysis; D004268:DNA-Binding Proteins / Q000235:genetics*; D015973:Gene Expression Regulation, Leukemic; D020672:I-kappa B Proteins / Q000378:metabolism; D051379:Mice; D008817:Mice, Mutant Strains; D016328:NF-kappa B / Q000378:metabolism*; D052002:NF-kappa B p50 Subunit; D011230:Precancerous Conditions / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D000073942:T-Cell Acute Lymphocytic Leukemia Protein 1; D013601:T-Lymphocytes / Q000737:chemistry / Q000378:metabolism; D013950:Thymus Gland / Q000473:pathology*; D013953:Thymus Neoplasms / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D051996:Transcription Factor RelA; D014157:Transcription Factors / Q000235:genetics*
D051792:Basic Helix-Loop-Helix Proteins; D015704:CD4 Antigens; D016827:CD8 Antigens; D004268:DNA-Binding Proteins; D020672:I-kappa B Proteins; D016328:NF-kappa B; D052002:NF-kappa B p50 Subunit; D011518:Proto-Oncogene Proteins; D000073942:T-Cell Acute Lymphocytic Leukemia Protein 1; D051996:Transcription Factor RelA; D014157:Transcription Factors; C489366:Tal1 protein, mouse