Format

Send to

Choose Destination
Oncogene. 2015 Oct 16;34(42):5341-51. doi: 10.1038/onc.2014.450. Epub 2015 Feb 2.

Hedgehog/GLI and PI3K signaling in the initiation and maintenance of chronic lymphocytic leukemia.

Author information

1
Department of Molecular Biology, Paris-Lodron University of Salzburg, Salzburg, Austria.
2
Laboratory for Immunological and Molecular Cancer Research, 3rd Medical Department with Haematology, Medical Oncology, Haemostaseology, Infectious Diseases, and Rheumatology, Oncologic Center, Paracelsus Medical University, Salzburg, Austria.
3
Salzburg Cancer Research Institute, Salzburg, Austria.
4
University of Michigan, Dermatology and Comprehensive Cancer Center, Ann Arbor, MI, USA.
5
APEIRON Biologics AG, Vienna, Austria.

Abstract

The initiation and maintenance of a malignant phenotype requires complex and synergistic interactions of multiple oncogenic signals. The Hedgehog (HH)/GLI pathway has been implicated in a variety of cancer entities and targeted pathway inhibition is of therapeutic relevance. Signal cross-talk with other cancer pathways including PI3K/AKT modulates HH/GLI signal strength and its oncogenicity. In this study, we addressed the role of HH/GLI and its putative interaction with the PI3K/AKT cascade in the initiation and maintenance of chronic lymphocytic leukemia (CLL). Using transgenic mouse models, we show that B-cell-specific constitutive activation of HH/GLI signaling either at the level of the HH effector and drug target Smoothened or at the level of the GLI transcription factors does not suffice to initiate a CLL-like phenotype characterized by the accumulation of CD5(+) B cells in the lymphatic system and peripheral blood. Furthermore, Hh/Gli activation in Pten-deficient B cells with activated Pi3K/Akt signaling failed to enhance the expansion of leukemic CD5(+) B cells, suggesting that genetic or epigenetic alterations leading to aberrant HH/GLI signaling in B cells do not suffice to elicit a CLL-like phenotype in mice. By contrast, we identify a critical role of GLI and PI3K signaling for the survival of human primary CLL cells. We show that combined targeting of GLI and PI3K/AKT/mTOR signaling can have a synergistic therapeutic effect in cells from a subgroup of CLL patients, thereby providing a basis for the evaluation of future combination therapies targeting HH/GLI and PI3K signaling in this common hematopoietic malignancy.

PMID:
25639866
PMCID:
PMC4430320
DOI:
10.1038/onc.2014.450
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Nature Publishing Group Icon for PubMed Central
Loading ...
Support Center