Notches, NFkappaBs and the making of T cell leukemia.

T cell lymphoblastic leukemia (T-ALL) is an aggressive hematological cancer frequent within pediatric ALL patients. Recent findings suggested that the transmembrane receptor NOTCH1 is the major oncogene for the majority of T-ALL cases. In these cases activating mutations of NOTCH1 are responsible for the transformation of developing T cell progenitors. These observations prompted us to study the mechanisms of Notch1-induced T cell transformation. Using parallel studies in T cell progenitors and established T-ALL lines we have demonstrated that the NFkappaB signaling pathway is targeted and induced by Notch1 activation. Our studies suggested that NFkappaB activation by Notch1 can be direct, as Notch1 can bind and activate the promoters of the RELB and NFkappaB2 factors and indirect, as Notch1 can form a complex with the NFkappaB kinase IKK. NFkappaB appears to be important for the development of the disease as suppression of the pathway antagonizes T cell transformation both in vitro and in vivo, using animal models of T-ALL. We believe that these findings could be important for the understanding of Notch1 signaling and the therapeutic treatment of T-ALL.