Medyouf, HindGusscott, SamuelWai, CarolNemirovsky, OksanaTrumpp, AndreasPflumio, FrancoiseCarboni, JoanGottardis, MarcoPollak, MichaelHolzenberger, MartinWeng, Andrew P.Wang, HongfangTseng, Jen-ChiehKung, AndrewAster, Jon2012-04-252011Medyouf, Hind, Samuel Gusscott, Hongfang Wang, Jen-Chieh Tseng, Carol Wai, Oksana Nemirovsky, Andreas Trumpp, et al. 2011. High-level IGF1R expression is required for leukemia-initiating cell activity in T-ALL and is supported by Notch signaling. Journal of Experimental Medicine 208(9): 1809-1822.0022-1007http://nrs.harvard.edu/urn-3:HUL.InstRepos:8615964T cell acute lymphoblastic leukemia (T-ALL) is an aggressive cancer of immature T cells that often shows aberrant activation of Notch1 and PI3K–Akt pathways. Although mutations that activate PI3K–Akt signaling have previously been identified, the relative contribution of growth factor-dependent activation is unclear. We show here that pharmacologic inhibition or genetic deletion of insulin-like growth factor 1 receptor (IGF1R) blocks the growth and viability of T-ALL cells, whereas moderate diminution of IGF1R signaling compromises leukemia-initiating cell (LIC) activity as defined by transplantability in syngeneic/congenic secondary recipients. Furthermore, IGF1R is a Notch1 target, and Notch1 signaling is required to maintain IGF1R expression at high levels in T-ALL cells. These findings suggest effects of Notch on LIC activity may be mediated in part by enhancing the responsiveness of T-ALL cells to ambient growth factors, and provide strong rationale for use of IGF1R inhibitors to improve initial response to therapy and to achieve long-term cure of patients with T-ALL.en-USJournal Article2012-04-2510.1084/jem.20110121