FBW7 ubiquitin ligase complex as a tumor suppressor in T cell leukemia

JEM © The Rockefeller University Press $15.00 Vol. 204, No. 8, August 6, 2007 1825-1835 www.jem.org/cgi/doi/ 1825 10.1084/jem.20070872 T cell acute lymphoblastic leukemia (T-ALL) is a disease induced by malignant transformation of T lymphocytes that affl icts mainly children and adolescents ( 1 ). Although treatment outcome in T-ALL has improved in recent years, patients with relapsed disease continue to have dismal prognosis, despite the use of protocols involving hematopoietic stem cell transplantation. It is thus very important to identify and study the molecular pathways that control both induction of transformation and treatment resistance in this particular type of leukemia. Recent compelling evidence demonstrated that activating mutations in the NOTCH1 gene are the trigger for cell transformation in the majority of T-ALL patients. Notch1 is a transmembrane receptor that controls the diff erentiation of multiple cell types, including cells of the immune system ( 2 ). More specifi cally, signaling through the NOTCH1 receptor orchestrates the development of T lymphocytes from uncommitted hematopoietic stem cells ( 3 – 5 ). Although NOTCH1 signaling is required for T cell development ( 6, 7 ), aberrant activation of the pathway can lead to disease; 50% of T-ALL cases harbor activating mutations in the NOTCH1 gene ( 8 ). Similar mutations were found in several mouse models of T cell leukemia ( 9 – 12 ). Very recent evidence showed that NOTCH1 pathway activation can induce multiple downstream signaling pathways and genes/ targets, including the NF-kB pathway ( 13 – 15 ) and the transcription factor c-Myc ( 16 – 18 ). The majority of the T-ALL NOTCH1-activating mutations truncate the C terminus of the protein, called the PEST domain because of the high frequency of P-E-S-T amino acids. As the PEST domain is believed to be essential for proteasome-dependent degradation of NOTCH1, these fi ndings suggest that NOTCH1 protein stability could be an important regulator of intracellular signaling thresholds and that abrogation CORRESPONDENCE Iannis Aifantis: [email protected]