NOTCH1 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(+) (double-positive, DP) cells by preventing normal surface expression of the T-cell receptor alphabeta (TCRalphabeta) complex. SCL-induced immature DP cells were further characterized by up-regulated NOTCH1 and generated noncycling polyclonal CD8(+)TCRbeta(low) 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.
Göthert
Joachim R
JR
Department of Hematology, University Hospital, Essen, Germany.joachim.goethert@uni-due.de
Brake
Rachael L
RL
Smeets
Monique
M
Dührsen
Ulrich
U
Begley
C Glenn
CG
Izon
David J
DJ
D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics*; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology; D002470:Cell Survival; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism*; D019674:Genes, T-Cell Receptor beta; D015458:Leukemia, T-Cell / Q000235:genetics*; D051379:Mice; D008822:Mice, Transgenic; D008954:Models, Biological; D009924:Organ Culture Techniques; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D051881:Receptor, Notch1 / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D000073942:T-Cell Acute Lymphocytic Leukemia Protein 1; D013950:Thymus Gland / Q000166:cytology / Q000196:embryology
D051792:Basic Helix-Loop-Helix Proteins; D011518:Proto-Oncogene Proteins; D051881:Receptor, Notch1; D000073942:T-Cell Acute Lymphocytic Leukemia Protein 1; C497762:Notch1 protein, mouse; C489366:Tal1 protein, mouse