title: Hedgehog/GLI and PI3K signaling in the initiation and maintenance of chronic lymphocytic leukemia.
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.
authors: Department of Molecular Biology, Paris-Lodron University of Salzburg, Salzburg, Austria.
authors: D
authors: D
authors: Kern
authors: Department of Molecular Biology, Paris-Lodron University of Salzburg, Salzburg, Austria.
authors: G
authors: G
authors: Regl
authors: 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.|Salzburg Cancer Research Institute, Salzburg, Austria.
authors: S W
authors: SW
authors: Hofbauer
authors: 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.|Salzburg Cancer Research Institute, Salzburg, Austria.
authors: P
authors: P
authors: Altenhofer
authors: Department of Molecular Biology, Paris-Lodron University of Salzburg, Salzburg, Austria.
authors: G
authors: G
authors: Achatz
authors: University of Michigan, Dermatology and Comprehensive Cancer Center, Ann Arbor, MI, USA.
authors: A
authors: A
authors: Dlugosz
authors: Department of Molecular Biology, Paris-Lodron University of Salzburg, Salzburg, Austria.|APEIRON Biologics AG, Vienna, Austria.
authors: H
authors: H
authors: Schnidar
authors: 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.|Salzburg Cancer Research Institute, Salzburg, Austria.
authors: R
authors: R
authors: Greil
authors: 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.|Salzburg Cancer Research Institute, Salzburg, Austria.
authors: T N
authors: TN
authors: Hartmann
authors: Department of Molecular Biology, Paris-Lodron University of Salzburg, Salzburg, Austria.
authors: F
authors: F
authors: Aberger
mesh_terms: D000818:Animals; D018941:Antigens, CD19 / Q000032:analysis; D001402:B-Lymphocytes / Q000276:immunology; D018956:CD5 Antigens / Q000032:analysis; D053823:Hedgehog Proteins / Q000502:physiology*; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy / Q000209:etiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D015513:Oncogene Proteins / Q000037:antagonists & inhibitors / Q000502:physiology*; D051059:PTEN Phosphohydrolase / Q000502:physiology; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D043562:Receptors, G-Protein-Coupled / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*; D000072086:Smoothened Receptor; D015534:Trans-Activators / Q000037:antagonists & inhibitors / Q000502:physiology*; D000071676:Zinc Finger Protein GLI1
chemical_list: D018941:Antigens, CD19; D018956:CD5 Antigens; D053823:Hedgehog Proteins; D015513:Oncogene Proteins; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D043562:Receptors, G-Protein-Coupled; D000072086:Smoothened Receptor; D015534:Trans-Activators; D000071676:Zinc Finger Protein GLI1; C491022:Smo protein, mouse
references: J Invest Dermatol. 2011 Aug;131(8):1735-44
references: 21430703
references: Science. 2007 Jul 20;317(5836):372-6
references: 17641202
references: Oncogene. 2007 Aug 2;26(35):5163-8
references: 17310984
references: Nat Med. 2007 Aug;13(8):944-51
references: 17632527
references: Psychoneuroendocrinology. 2007 Aug;32 Suppl 1:S52-6
references: 17619088
references: Nat Cell Biol. 2007 Sep;9(9):1005-9
references: 17762891
references: Trends Cell Biol. 2007 Sep;17(9):438-47
references: 17845852
references: Immunity. 2001 May;14(5):523-34
references: 11371355
references: Methods Mol Biol. 2007;397:67-78
references: 18025714
references: J Mol Med (Berl). 2008 May;86(5):541-52
references: 18297255
references: Mol Cancer Ther. 2008 Jun;7(6):1680-7
references: 18566239
references: Mol Cancer Ther. 2008 Jul;7(7):1851-63
references: 18606717
references: Cancer Cell. 2008 Sep 9;14(3):238-49
references: 18772113
references: J Med Chem. 2008 Sep 25;51(18):5522-32
references: 18754654
references: Nat Rev Cancer. 2008 Oct;8(10):743-54
references: 18813320
references: Mol Cancer Res. 2008 Dec;6(12):1928-36
references: 19074837
references: Genes Dev. 2009 Jan 1;23(1):24-36
references: 19136624
references: Cancer Res. 2009 Feb 15;69(4):1284-92
references: 19190345
references: J Biol Chem. 2009 Apr 3;284(14):9074-82
references: 19189974
references: Nature. 2009 Apr 9;458(7239):776-9
references: 19169242
references: Trends Pharmacol Sci. 2009 Jun;30(6):303-12
references: 19443052
references: Nat Rev Clin Oncol. 2009 Jul;6(7):405-18
references: 19488076
references: Mol Cancer. 2009;8:40
references: 19555497
references: N Engl J Med. 2009 Sep 17;361(12):1173-8
references: 19726761
references: N Engl J Med. 2009 Sep 17;361(12):1164-72
references: 19726763
references: Mod Pathol. 2009 Oct;22(10):1312-20
references: 19593328
references: Blood. 2009 Oct 15;114(16):3367-75
references: 19636060
references: Science. 2009 Oct 23;326(5952):572-4
references: 19726788
references: Haematologica. 2009 Dec;94(12):1698-707
references: 19815839
references: Nat Rev Cancer. 2010 Jan;10(1):37-50
references: 19956173
references: Biochim Biophys Acta. 2010 Apr;1805(2):181-208
references: 20085802
references: J Mol Cell Biol. 2010 Apr;2(2):84-95
references: 20083481
references: Blood. 2010 Mar 25;115(12):2391-6
references: 20107231
references: Proc Natl Acad Sci U S A. 2010 Jul 27;107(30):13432-7
references: 20624968
references: Oncogene. 2010 Sep 2;29(35):4885-95
references: 20603613
references: Blood. 2010 Sep 23;116(12):2078-88
references: 20522708
references: Sci Transl Med. 2010 Sep 29;2(51):51ra70
references: 20881279
references: J Clin Invest. 2011 Jan;121(1):148-60
references: 21183792
references: Trends Immunol. 2011 Apr;32(4):139-45
references: 21388881
references: Biochem Biophys Res Commun. 2011 Apr 8;407(2):360-5
references: 21396911
references: Nat Rev Genet. 2011 Jun;12(6):393-406
references: 21502959
references: Annu Rev Cell Dev Biol. 2011;27:513-37
references: 21801010
references: Blood. 2011 Oct 20;118(16):4313-20
references: 21816833
references: Front Biosci (Landmark Ed). 2012;17:90-9
references: 22201734
references: Blood. 2012 Jan 26;119(4):997-1007
references: 22130798
references: Vitam Horm. 2012;88:25-54
references: 22391298
references: Vitam Horm. 2012;88:55-72
references: 22391299
references: EMBO Mol Med. 2012 Mar;4(3):218-33
references: 22294553
references: Cancer Cell. 2012 Mar 20;21(3):374-87
references: 22439934
references: N Engl J Med. 2012 Jun 7;366(23):2171-9
references: 22670903
references: N Engl J Med. 2012 Jun 7;366(23):2180-8
references: 22670904
references: Gastroenterology. 2013 Jan;144(1):134-144.e6
references: 23041331
references: Nature. 2013 Feb 28;494(7438):484-8
references: 23446420
references: Clin Cancer Res. 2013 Mar 15;19(6):1422-32
references: 23319824
references: Clin Cancer Res. 2013 Mar 15;19(6):1309-11
references: 23382113
references: J Hematol Oncol. 2013;6:36
references: 23680477
references: Nat Med. 2013 Nov;19(11):1518-23
references: 24076665
references: N Engl J Med. 2014 Mar 13;370(11):997-1007
references: 24450857
references: Blood. 2014 May 29;123(22):3390-7
references: 24615777
references: Nature. 2014 Jul 3;511(7507):90-3
references: 24870236
references: Semin Cell Dev Biol. 2014 Sep;33:93-104
references: 24852887
references: Genes Dev. 2001 Dec 1;15(23):3059-87
references: 11731473
references: Proc Natl Acad Sci U S A. 2002 May 14;99(10):6955-60
references: 12011454
references: J Exp Med. 2003 Mar 3;197(5):657-67
references: 12615906
references: Trends Immunol. 2003 Mar;24(3):104-8
references: 12615201
references: EMBO J. 2003 Jun 2;22(11):2741-51
references: 12773389
references: Genes Dev. 2004 Apr 15;18(8):937-51
references: 15107405
references: Biochem J. 1993 Dec 1;296 ( Pt 2):297-301
references: 8257416
references: Nature. 1994 Jun 30;369(6483):756-8
references: 8008069
references: Nucleic Acids Res. 1997 Mar 15;25(6):1317-8
references: 9092650
references: N Engl J Med. 1998 Nov 5;339(19):1341-8
references: 9801394
references: Leuk Res. 1999 Feb;23(2):127-36
references: 10071128
references: Nature. 2004 Nov 18;432(7015):324-31
references: 15549094
references: Cancer. 2005 Jan 15;103(2):216-28
references: 15578683
references: Nat Rev Mol Cell Biol. 2005 Apr;6(4):306-17
references: 15803137
references: Proc Natl Acad Sci U S A. 2005 Aug 9;102(32):11325-30
references: 16061793
references: Nature. 2005 Oct 13;437(7061):1018-21
references: 16136078
references: Cancer Res. 2006 Jan 15;66(2):839-45
references: 16424016
references: Proc Natl Acad Sci U S A. 2006 Mar 21;103(12):4505-10
references: 16537363
references: Mol Cell Biol. 2006 Aug;26(16):6283-98
references: 16880536
references: Genes Dev. 2006 Nov 15;20(22):3161-73
references: 17114586
references: Proc Natl Acad Sci U S A. 2007 Mar 6;104(10):4048-53
references: 17360475
references: Proc Natl Acad Sci U S A. 2007 Apr 3;104(14):5895-900
references: 17392427
references: Proc Natl Acad Sci U S A. 2007 May 15;104(20):8455-60
references: 17494766
references: Cancer Res. 2007 Jul 15;67(14):6981-6
references: 17638910