title: High-level IGF1R expression is required for leukemia-initiating cell activity in T-ALL and is supported by Notch signaling.
abstract: T 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.
authors.affiliation: Terry Fox Laboratory/Department of Pathology, BC Cancer Agency, Vancouver, BC, V52 1L3 Canada. h.medyouf@dkfz-heidelberg.de
authors.forename: Hind
authors.initials: H
authors.lastname: Medyouf
authors.forename: Samuel
authors.initials: S
authors.lastname: Gusscott
authors.forename: Hongfang
authors.initials: H
authors.lastname: Wang
authors.forename: Jen-Chieh
authors.initials: JC
authors.lastname: Tseng
authors.forename: Carol
authors.initials: C
authors.lastname: Wai
authors.forename: Oksana
authors.initials: O
authors.lastname: Nemirovsky
authors.forename: Andreas
authors.initials: A
authors.lastname: Trumpp
authors.forename: Francoise
authors.initials: F
authors.lastname: Pflumio
authors.forename: Joan
authors.initials: J
authors.lastname: Carboni
authors.forename: Marco
authors.initials: M
authors.lastname: Gottardis
authors.forename: Michael
authors.initials: M
authors.lastname: Pollak
authors.forename: Andrew L
authors.initials: AL
authors.lastname: Kung
authors.forename: Jon C
authors.initials: JC
authors.lastname: Aster
authors.forename: Martin
authors.initials: M
authors.lastname: Holzenberger
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Weng
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D016513:Mice, SCID; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics / Q000378:metabolism* / Q000628:therapy; D017526:Receptor, IGF Type 1 / Q000096:biosynthesis* / Q000235:genetics; D051881:Receptor, Notch1 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: C497761:NOTCH1 protein, human; C497762:Notch1 protein, mouse; D051881:Receptor, Notch1; D019869:Phosphatidylinositol 3-Kinases; D017526:Receptor, IGF Type 1