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J Exp Med. 2011 Aug 29;208(9):1809-22. doi: 10.1084/jem.20110121. Epub 2011 Aug 1.

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

Author information

1
Terry Fox Laboratory/Department of Pathology, BC Cancer Agency, Vancouver, BC, V52 1L3 Canada. h.medyouf@dkfz-heidelberg.de

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.

PMID:
21807868
PMCID:
PMC3171095
DOI:
10.1084/jem.20110121
[Indexed for MEDLINE]
Free PMC Article

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