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Hedgehog/GLI and PI3K signaling in the initiation and maintenance of chronic lymphocytic leukemia
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 o...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group
2015
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4430320/ https://www.ncbi.nlm.nih.gov/pubmed/25639866 http://dx.doi.org/10.1038/onc.2014.450 |
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author | Kern, D Regl, G Hofbauer, S W Altenhofer, P Achatz, G Dlugosz, A Schnidar, H Greil, R Hartmann, T N Aberger, F |
author_facet | Kern, D Regl, G Hofbauer, S W Altenhofer, P Achatz, G Dlugosz, A Schnidar, H Greil, R Hartmann, T N Aberger, F |
author_sort | Kern, D |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-4430320 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2015 |
publisher | Nature Publishing Group |
record_format | MEDLINE/PubMed |
spelling | pubmed-44303202015-11-25 Hedgehog/GLI and PI3K signaling in the initiation and maintenance of chronic lymphocytic leukemia Kern, D Regl, G Hofbauer, S W Altenhofer, P Achatz, G Dlugosz, A Schnidar, H Greil, R Hartmann, T N Aberger, F Oncogene Original Article 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. Nature Publishing Group 2015-10-16 2015-02-02 /pmc/articles/PMC4430320/ /pubmed/25639866 http://dx.doi.org/10.1038/onc.2014.450 Text en Copyright © 2015 Macmillan Publishers Limited http://creativecommons.org/licenses/by-nc-sa/4.0/ This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/4.0/ |
spellingShingle | Original Article Kern, D Regl, G Hofbauer, S W Altenhofer, P Achatz, G Dlugosz, A Schnidar, H Greil, R Hartmann, T N Aberger, F Hedgehog/GLI and PI3K signaling in the initiation and maintenance of chronic lymphocytic leukemia |
title | Hedgehog/GLI and PI3K signaling in the initiation and maintenance of chronic lymphocytic leukemia |
title_full | Hedgehog/GLI and PI3K signaling in the initiation and maintenance of chronic lymphocytic leukemia |
title_fullStr | Hedgehog/GLI and PI3K signaling in the initiation and maintenance of chronic lymphocytic leukemia |
title_full_unstemmed | Hedgehog/GLI and PI3K signaling in the initiation and maintenance of chronic lymphocytic leukemia |
title_short | Hedgehog/GLI and PI3K signaling in the initiation and maintenance of chronic lymphocytic leukemia |
title_sort | hedgehog/gli and pi3k signaling in the initiation and maintenance of chronic lymphocytic leukemia |
topic | Original Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4430320/ https://www.ncbi.nlm.nih.gov/pubmed/25639866 http://dx.doi.org/10.1038/onc.2014.450 |
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