High-level IGF1R expression is required for leukemia-initiating cell activity in T-ALL and is supported by Notch signaling

• DOI: 10.1084/jem.20110121
• Publication Date: 2011-08-02T02:39:59Z
• Authors: Hind Medyouf; Samuel Gusscott; Hongfang Wang; Jen-Chieh Tseng; Carol Wai; Oksana Nemirovsky; Andreas Trumpp; Francoise Pflumio; Joan Carboni; Marco Gottardis; Michael Pollak; Andrew L. Kung; Jon C. Aster; Martin Holzenberger; Andrew P. Weng
• Keywords: 0301 basic medicine; 570; 0303 health sciences; Gene Expression Regulation, Leukemic; 610; Mice, Nude; Mice, SCID; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma; Article; Receptor, IGF Type 1; Mice; Phosphatidylinositol 3-Kinases; 03 medical and health sciences; Cell Line, Tumor; Animals; Humans; Receptor, Notch1; Signal Transduction

T cell acute lymphoblastic leukemia (T-ALL) is an aggressive cancer of immature cells that often shows aberrant activation Notch1 and PI3K–Akt pathways. Although mutations activate signaling have previously been identified, the relative contribution growth factor-dependent unclear. We show here pharmacologic inhibition or genetic deletion insulin-like factor 1 receptor (IGF1R) blocks viability T-ALL cells, whereas moderate diminution IGF1R compromises leukemia-initiating (LIC) activity as defined by transplantability in syngeneic/congenic secondary recipients. Furthermore, a target, required to maintain expression at high levels cells. These findings suggest effects Notch on LIC may be mediated part enhancing responsiveness ambient factors, provide strong rationale for use inhibitors improve initial response therapy achieve long-term cure patients with T-ALL.