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High-level IGF1R expression is required for leukemia-initiating cell activity in T-ALL and is supported by Notch signaling
- Source :
- The Journal of Experimental Medicine
- Publication Year :
- 2011
- Publisher :
- Rockefeller University Press, 2011.
-
Abstract
- Notch-driven expression of IGF1R promotes the growth, viability, and transplantability of T-ALL cells.<br />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.
- Subjects :
- medicine.medical_treatment
T cell
Immunology
Cell
Notch signaling pathway
Mice, Nude
Mice, SCID
Biology
Precursor T-Cell Lymphoblastic Leukemia-Lymphoma
Article
Receptor, IGF Type 1
Mice
Phosphatidylinositol 3-Kinases
03 medical and health sciences
0302 clinical medicine
Cell Line, Tumor
medicine
Animals
Humans
Immunology and Allergy
Receptor, Notch1
Insulin-like growth factor 1 receptor
030304 developmental biology
0303 health sciences
Gene Expression Regulation, Leukemic
Growth factor
Cell Biology
medicine.disease
3. Good health
body regions
Leukemia
surgical procedures, operative
medicine.anatomical_structure
Cell culture
030220 oncology & carcinogenesis
Cancer research
Signal transduction
Signal Transduction
030215 immunology
Subjects
Details
- ISSN :
- 15408140 and 00219525
- Volume :
- 194
- Database :
- OpenAIRE
- Journal :
- The Journal of Cell Biology
- Accession number :
- edsair.doi.dedup.....3df4c846c4d3ab5f5827a982224086da