NF- B activation in premalignant mouse tal-1/scl thymocytes and tumors
نویسندگان
چکیده
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 NFB activation. Increased NFB activity is also observed in tal-1/scl tumors and bcl-2 is overexpressed. To examine the contribution of NFB to tal-1/ scl tumor growth in vivo, we expressed a mutant form of I B in tal-1/scl tumor cells. Although expression of mutant I B inhibited the tumor necrosis factor alpha (TNF)–induced NFB response, it had no effect on tumor growth in mice. These data suggest that NFB 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. (Blood. 2003;102:2593-2596)
منابع مشابه
Disordered T-cell development and T-cell malignancies in SCL LMO1 double-transgenic mice: parallels with E2A-deficient mice.
The gene most commonly activated by chromosomal rearrangements in patients with T-cell acute lymphoblastic leukemia (T-ALL) is SCL/tal. In collaboration with LMO1 or LMO2, the thymic expression of SCL/tal leads to T-ALL at a young age with a high degree of penetrance in transgenic mice. We now show that SCL LMO1 double-transgenic mice display thymocyte developmental abnormalities in terms of pr...
متن کاملConstitutive IKK2 activation in intestinal epithelial cells induces intestinal tumors in mice.
Many cancers display increased NF-κB activity, and NF-κB inhibition is known to diminish tumor development in multiple mouse models, supporting an important role of NF-κB in carcinogenesis. NF-κB activation in premalignant or cancer cells is believed to promote tumor development mainly by protecting these cells from apoptosis. However, it remains unclear to what extent NF-κB activation exhibits...
متن کاملThe T Cell Leukemia Oncoprotein SCL/tal-1 Is Essential for Development of All Hematopoietic Lineages
The T cell leukemia oncoprotein SCL/tal-1, a basic-helix-loop-helix transcription factor, is required for production of embryonic red blood cells in the mouse yolk sac. To define roles in other lineages, we studied the hematopoietic potential of homozygous mutant SCL/tal-1 -/- embryonic stem cells upon in vitro differentiation and in vivo in chimeric mice. Here we show that in the absence of SC...
متن کاملNOTCH1 pathway activation is an early hallmark of SCL T leukemogenesis.
The acquired activation of stem cell leukemia (SCL) during T lymphopoiesis is a common event in T-cell acute lymphoblastic leukemia (T-ALL). Here, we generated tamoxifen (TAM)-inducible transgenic mice (lck-ER(T2)-SCL) to study the consequences of acquired SCL activation during T-cell development. Aberrant activation of SCL in thymocytes resulted in the accumulation of immature CD4(+)CD8(+) (do...
متن کاملInhibition of cellular differentiation by the SCL/tal oncoprotein: transcriptional repression by an Id-like mechanism.
In cases of T-cell acute lymphoblastic leukemia (T-ALL), the basic helix-loop-helix (bHLH) oncogene SCL/tal undergoes frequent rearrangements activating ectopic expression. Despite the compelling epidemiological association of SCL/tal expression with T-ALL, no specific transforming function has been attributable to the protein product. However, investigators have recently demonstrated that forc...
متن کامل