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 Blood, 15 November 2007, Vol. 110, No. 10, pp. 3753-3762.
Prepublished online as a Blood First Edition Paper on August 13, 2007; DOI 10.1182/blood-2006-12-063644.

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NEOPLASIA

NOTCH1 pathway activation is an early hallmark of SCL T leukemogenesis

Joachim R. Göthert1,2, Rachael L. Brake2, Monique Smeets2, Ulrich Dührsen1, C. Glenn Begley2, and David J. Izon2

1 Department of Hematology, University Hospital, Essen, Germany; and 2 Division of Cancer Biology, Telethon Institute for Child Health Research, Centre for Child Health Research, Subiaco, Australia

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-ERT2-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+ (double-positive, DP) cells by preventing normal surface expression of the T-cell receptor {alpha}ß (TCR{alpha}ß) complex. SCL-induced immature DP cells were further characterized by up-regulated NOTCH1 and generated noncycling polyclonal CD8+TCRßlow cells. The prevalence of these cells was SCL dependent because TAM withdrawal resulted in their disappearance. Furthermore, we observed that SCL activation led to a dramatic up-regulation of NOTCH1 target genes (Hes-1, Deltex1, and CD25) in thymocytes. Strikingly, NOTCH1 target gene up-regulation was already observed after short-term SCL induction, implying that enhanced NOTCH signaling is mediated by SCL and is not dependent on secondary genetic events. These data represent the basis for a novel pathway of SCL-induced leukemogenesis and provide a functional link between SCL and NOTCH1 during this process.


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