title: Constitutive activation of Pim1 kinase is a therapeutic target for adult T-cell leukemia.
abstract: Human T-cell leukemia virus type 1 (HTLV-1)-associated adult T-cell leukemia and T-cell lymphoma (ATL) are aggressive diseases with poor prognoses, limited therapeutic options, and no curative treatment. In this study, we used a mouse model of ATL and restored expression of the microRNA, miR-124a, to identify in vivo downstream effectors responsible for its tumor-suppressive functions in ATL cells. Our results revealed that STAT3, a direct target of miR-124a, is constitutively activated in HTLV-I-transformed cells and ATL cells, and activating STAT3 mutations were detected in 25.5% of primary ATL patients. Interestingly, we found that the STAT3 downstream kinase effector, Pim1, is constitutively activated in ATL cells. The dependence of ATL cells to Pim1 activity was demonstrated using 2 Pim1 small inhibitors, SMI-4a and AZD1208. These studies indicated that HTLV-I-transformed and ATL cells, but not normal peripheral blood mononuclear cells, are highly sensitive to AZD1208, and the inhibition of Pim1 signaling triggers an apoptotic signal in leukemic cells. Finally, preclinical testing of AZD1208 in a mouse model of ATL resulted in significant prevention of tumor growth in vivo. In conclusion, our studies suggest that constitutive activation of the STAT3-Pim1 pathway represents a novel therapeutic target for the treatment of ATL.
authors.affiliation: Department of Pathology and Laboratory Medicine, Center for Viral Oncology, University of Kansas Medical Center, Kansas City, KS.
authors.forename: Marcia
authors.initials: M
authors.lastname: Bellon
authors.affiliation: Department of Pathology and Laboratory Medicine, Center for Viral Oncology, University of Kansas Medical Center, Kansas City, KS.
authors.forename: Ling
authors.initials: L
authors.lastname: Lu
authors.affiliation: Department of Pathology and Laboratory Medicine, Center for Viral Oncology, University of Kansas Medical Center, Kansas City, KS.
authors.forename: Christophe
authors.initials: C
authors.lastname: Nicot
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001713:Biphenyl Compounds / Q000494:pharmacology; D002448:Cell Adhesion; D002461:Cell Line, Transformed; D004789:Enzyme Activation / Q000235:genetics; D015973:Gene Expression Regulation, Leukemic / Q000235:genetics; D020868:Gene Silencing; D057809:HEK293 Cells; D015368:Human T-lymphotropic virus 1 / Q000502:physiology; D006801:Humans; D051379:Mice; D035683:MicroRNAs / Q000494:pharmacology*; D058990:Molecular Targeted Therapy; D009154:Mutation; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors*; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051573:Proto-Oncogene Proteins c-pim-1 / Q000037:antagonists & inhibitors*; D050796:STAT3 Transcription Factor / Q000502:physiology; D015398:Signal Transduction; D053778:Thiazolidines / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
chemical_list: C587575:AZD1208; D001713:Biphenyl Compounds; C509207:MIRN124 microRNA, human; D035683:MicroRNAs; D009363:Neoplasm Proteins; D047428:Protein Kinase Inhibitors; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D053778:Thiazolidines; C496634:PIM1 protein, human; D051573:Proto-Oncogene Proteins c-pim-1
references.citation: Immunol Rev. 2012 Mar;246(1):286-310
references.pmid: 22435562
references.citation: Oncogene. 2012 Feb 16;31(7):918-28
references.pmid: 21743487
references.citation: BMC Cancer. 2015 Apr 19;15:306
references.pmid: 25928665
references.citation: Viruses. 2015 Jul 20;7(7):4047-74
references.pmid: 26205403
references.citation: Blood. 2011 Feb 10;117(6):1938-46
references.pmid: 21106989
references.citation: Cancer Res. 2009 May 15;69(10):4443-53
references.pmid: 19435910
references.citation: Blood. 2013 Jun 20;121(25):5045-54
references.pmid: 23660959
references.citation: Oncotarget. 2014 Sep 30;5(18):8503-14
references.pmid: 25238262
references.citation: Neoplasia. 2015 May;17(5):449-62
references.pmid: 26025667
references.citation: Blood. 2009 May 14;113(20):4914-7
references.pmid: 19246560
references.citation: Proc Natl Acad Sci U S A. 1982 Mar;79(6):2031-5
references.pmid: 6979048
references.citation: Proc Natl Acad Sci U S A. 1980 Dec;77(12):7415-9
references.pmid: 6261256
references.citation: N Engl J Med. 2012 May 17;366(20):1905-13
references.pmid: 22591296
references.citation: Blood. 2010 Jan 28;115(4):824-33
references.pmid: 19965690
references.citation: Leukemia. 2015 Mar;29(3):586-97
references.pmid: 25134459
references.citation: Proc Natl Acad Sci U S A. 2015 Oct 6;112(40):12480-5
references.pmid: 26396258
references.citation: Science. 1995 Jul 7;269(5220):79-81
references.pmid: 7604283
references.citation: Blood. 2014 Jan 2;123(1):15-25
references.pmid: 24169824
references.citation: Proc Natl Acad Sci U S A. 1997 Dec 9;94(25):13897-902
references.pmid: 9391124
references.citation: Clin Cancer Res. 2013 Apr 15;19(8):1933-40
references.pmid: 23406773
references.citation: Blood. 2015 Dec 10;126(24):2570-7
references.pmid: 26361794
references.citation: Int J Oncol. 2015 Feb;46(2):798-808
references.pmid: 25531908
references.citation: Curr Oncol Rep. 2013 Oct;15(5):457-64
references.pmid: 23943384
references.citation: Carcinogenesis. 2010 May;31(5):766-76
references.pmid: 19843643
references.citation: Nat Genet. 2015 Nov;47(11):1304-15
references.pmid: 26437031
references.citation: Blood. 2012 Oct 11;120(15):3048-57
references.pmid: 22859607
references.citation: J Clin Invest. 2005 May;115(5):1361-8
references.pmid: 15864353
references.citation: Rev Clin Exp Hematol. 2003 Dec;7(4):336-61
references.pmid: 15129647
references.citation: Proc Natl Acad Sci U S A. 2015 Sep 1;112(35):11030-5
references.pmid: 26283355
references.citation: J Transl Med. 2011 Nov 14;9:197
references.pmid: 22082000
references.citation: Cancer Cell. 2012 Jan 17;21(1):121-35
references.pmid: 22264793
references.citation: Blood. 1988 Jan;71(1):263-6
references.pmid: 2891388
references.citation: PLoS One. 2011 Apr 22;6(4):e19027
references.pmid: 21544199
references.citation: Proc Natl Acad Sci U S A. 2007 May 1;104(18):7391-6
references.pmid: 17463090
references.citation: J Clin Oncol. 2009 Jan 20;27(3):453-9
references.pmid: 19064971
references.citation: Blood. 2014 Feb 6;123(6):905-13
references.pmid: 24363397
references.citation: Proc Natl Acad Sci U S A. 2010 Sep 21;107(38):16619-24
references.pmid: 20823234
references.citation: Oncogene. 2000 May 15;19(21):2496-504
references.pmid: 10851048
references.citation: Blood. 1995 Nov 15;86(10):3619-39
references.pmid: 7579327