Submitted December 19, 2006
Accepted August 11, 2007
NOTCH1 pathway activation is an early hallmark of SCL T-leukemogenesis
Joachim R Gothert*, Rachael L Brake, Monique Smeets, Ulrich Duhrsen, C Glenn Begley, and David J Izon
Department of Hematology, University Hospital, Essen, Germany
Division of Cancer Biology, Telethon Institute for Child Health Research, Centre for Child Health Research, Subiaco, Australia
* Corresponding author; email: joachim.goethert{at}uni-due.de.
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 (TCR)-
complex. SCL induced immature DP cells were further characterized by up-regulated NOTCH1 and generated non-cycling polyclonal CD8+TCRlow cells. The prevalence of these cells was SCL-dependent because TAM-withdrawal resulted in their disappearance. Furthermore, we observed that SCL activation lead to a dramatic upregulation of NOTCH1 target genes (Hes-1, Deltex1 and CD25) in thymocytes. Strikingly, NOTCH1 target gene upregulation 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.
