STAT3 as a possible therapeutic target in human malignancies: Lessons from acute myeloid leukemia

Expert Review of Hematology

Volumn 8, Issue 1, 2015, Pages 29-41

  Bruserud, Oystein ^a,b   Nepstad, Ina ^b   Hauge, Michelle ^b   Hatfield, Kimberley Joanne ^b   Reikvam, Håkon ^a,b  

^a HAUKELAND UNIVERSITY HOSPITAL   (Norway)

^b UNIVERSITY OF BERGEN   (Norway)

Author keywords

acute myeloid leukemia; clinical studies; mitochondria; phosphorylation; prognosis; STAT3; therapy; transcription

Indexed keywords

STAT3 PROTEIN;

ACUTE GRANULOCYTIC LEUKEMIA; ALLOGRAFT; AMINO TERMINAL SEQUENCE; APOPTOSIS; BINDING SITE; BONE MARROW CELL; CANCER DIAGNOSIS; CANCER PATIENT; CANCER PROGNOSIS; CELL DIFFERENTIATION; CELL MATURATION; CELL MOTILITY; CELL PROLIFERATION; CHEMOSENSITIZATION; DNA BINDING; GRAFT RECIPIENT; HEMATOPOIETIC CELL; HEMATOPOIETIC STEM CELL; HUMAN; IMMUNE RESPONSE; IMMUNOREGULATION; MALIGNANT NEOPLASTIC DISEASE; MICROTUBULE; MITOCHONDRION; NONHUMAN; PRIORITY JOURNAL; PROTEIN ANALYSIS; PROTEIN DOMAIN; PROTEIN EXPRESSION; PROTEIN FUNCTION; PROTEIN LOCALIZATION; PROTEIN MOTIF; PROTEIN PHOSPHORYLATION; PROTEIN PROCESSING; PROTEIN STRUCTURE; REVIEW; ANIMAL; GENETICS; LEUKEMIA, MYELOID, ACUTE; METABOLISM; MOLECULARLY TARGETED THERAPY; PROGNOSIS; SIGNAL TRANSDUCTION;

ANIMALS; HUMANS; LEUKEMIA, MYELOID, ACUTE; MOLECULAR TARGETED THERAPY; PROGNOSIS; SIGNAL TRANSDUCTION; STAT3 TRANSCRIPTION FACTOR;

EID: 84920774454     PISSN: 17474086     EISSN: 17474094     Source Type: Journal    
DOI: 10.1586/17474086.2015.971005     Document Type: Review

References (109)

1. Fagard R, Metelev V, Souissi I, Baran-Marszak F. STAT3 inhibitors for cancer therapy: have all roads been explored? Jak-Stat 2013;2(1):e22882
2. Sellier H, Rebillard A, Guette C, et al. How should we define STAT3 as an oncogene and as a potential target for therapy? Jak-Stat 2013;2(3):e24716
3. Frank DA. STAT3 as a central mediator of neoplastic cellular transformation. Cancer Lett 2007;251(2):199-210
4. Bar-Natan M, Nelson EA, Xiang M, Frank DA. STAT signaling in the pathogenesis and treatment of myeloid malignancies. Jak-Stat 2012;1(2):55-64
5. Hutchins AP, Diez D, Miranda-Saavedra D. Genomic and computational approaches to dissect the mechanisms of STAT3's universal and cell type-specific functions. Jak-Stat 2013;2(4):e25097
6. WHO. World Health Organization Classification of Tumors of Haematopoietic and Lymphoid Tissues. 4th Edition. International Agency for Cancer; Lyon: 2008
7. Yilmaz AF, Saydam G, Sahin F, Baran Y. Granulocytic sarcoma: a systematic review. Am J Blood Res 2013;3(4):265-70
8. Reikvam H, Hatfield KJ, Kittang AO, et al. Acute Myeloid Leukemia with the t(8;21) Translocation: clinical Consequences and Biological Implications. J Biomed Biotechnol 2011;2011:104631
9. Lowenberg B, Beck J, Graux C, et al. Gemtuzumab ozogamicin as postremission treatment in AML at 60 years of age or more: results of a multicenter phase 3 study. Blood 2010;115(13):2586-91
10. Dohner H, Estey EH, Amadori S, et al. Diagnosis and management of acute myeloid leukemia in adults: recommendations from an international expert panel, on behalf of the European LeukemiaNet. Blood 2010;115(3):453-74
11. Marcucci G, Mrozek K, Bloomfield CD. Molecular heterogeneity and prognostic biomarkers in adults with acute myeloid leukemia and normal cytogenetics. Curr Opin Hematol 2005;12(1):68-75
12. Marcucci G, Radmacher MD, Mrozek K, Bloomfield CD. MicroRNA expression in acute myeloid leukemia. Cur Hematol Malign Rep 2009;4(2):83-8
13. Mrozek K, Marcucci G, Paschka P, et al. Clinical relevance of mutations and gene-expression changes in adult acute myeloid leukemia with normal cytogenetics: are we ready for a prognostically prioritized molecular classification? Blood 2007;109(2): 431-48
14. Irish JM, Anensen N, Hovland R, et al. Flt3 Y591 duplication and Bcl-2 overexpression are detected in acute myeloid leukemia cells with high levels of phosphorylated wild-type p53. Blood 2007; 109(6):2589-96
15. Irish JM, Hovland R, Krutzik PO, et al. Single cell profiling of potentiated phospho-protein networks in cancer cells. Cell 2004;118(2):217-28
16. Tsykunova G, Reikvam H, Hovland R, Bruserud O. The surface molecule signature of primary human acute myeloid leukemia (AML) cells is highly associated with NPM1 mutation status. Leukemia 2012; 26(3):557-9
17. Skavland J, Jorgensen KM, Hadziavdic K, et al. Specific cellular signal-transduction responses to in vivo combination therapy with ATRA, valproic acid and theophylline in acute myeloid leukemia. Blood Cancer J 2011;1:e4
18. Anensen N, Hjelle SM, Van Belle W, et al. Correlation analysis of p53 protein isoforms with NPM1/FLT3 mutations and therapy response in acute myeloid leukemia. Oncogene 2012;31(12):1533-45
19. Reikvam H, Tamburini J, Skrede S, et al. Antileukaemic effect of PI3K-mTOR inhibitors in acute myeloid leukaemia-gene expression profiles reveal CDC25B expression as determinate of pharmacological effect. Br J Haematol 2014; 164(2):200-11
20. Reikvam H, Nepstad I, Bruserud O, Hatfield KJ. Pharmacological targeting of the PI3K/mTOR pathway alters the release of angioregulatory mediators both from primary human acute myeloid leukemia cells and their neighboring stromal cells. Oncotarget 2013;4(6):830-43
21. Redell MS, Ruiz MJ, Gerbing RB, et al. FACS analysis of Stat3/5 signaling reveals sensitivity to G-CSF and IL-6 as a significant prognostic factor in pediatric AML: a Children's Oncology Group report. Blood 2013;121(7):1083-93
22. Kornblau SM, Minden MD, Rosen DB, et al. Dynamic single-cell network profiles in acute myelogenous leukemia are associated with patient response to standard induction therapy. Clinl Cancer Res 2010; 16(14):3721-33
23. Reikvam H, Olsnes AM, Gjertsen BT, et al. Nuclear factor-kappaB signaling: a contributor in leukemogenesis and a target for pharmacological intervention in human acute myelogenous leukemia. Crit Rev Oncog 2009;15(1-2):1-41
24. Reikvam H, Ersvaer E, Bruserud O. Heat shock protein 90-a potential target in the treatment of human acute myelogenous leukemia. Curr Cancer Drug Targets 2009; 9(6):761-76
25. Redell MS, Ruiz MJ, Alonzo TA, et al. Stat3 signaling in acute myeloid leukemia: ligand-dependent and-independent activation and induction of apoptosis by a novel small-molecule Stat3 inhibitor. Blood 2011;117(21):5701-9
26. Reikvam H, Oyan AM, Kalland KH, et al. Differences in proliferative capacity of primary human acute myelogenous leukaemia cells are associated with altered gene expression profiles and can be used for subclassification of patients. Cell Prolif 2013;46(5):554-62
27. Bruserud O, Hovland R, Wergeland L, et al. Flt3-mediated signaling in human acute myelogenous leukemia (AML) blasts: a functional characterization of Flt3-ligand effects in AML cell populations with and without genetic Flt3 abnormalities. Haematologica 2003;88(4):416-28
28. Bruserud O, Ryningen A, Olsnes AM, et al. Subclassification of patients with acute myelogenous leukemia based on chemokine responsiveness and constitutive chemokine release by their leukemic cells. Haematologica 2007;92(3):332-41
29. Tsykunova G, Reikvam H, Ahmed AB, et al. Targeting of polo-like kinases and their cross talk with Aurora kinases-possible therapeutic strategies in human acute myeloid leukemia? Expert Opin Investig Drugs 2012;21(5):587-603
30. Lavecchia A, Di Giovanni C, Pesapane A, et al. Discovery of new inhibitors of Cdc25B dual specificity phosphatases by structure-based virtual screening. J Medl Chem 2012;55(9):4142-58
31. Hatfield K, Ryningen A, Corbascio M, Bruserud O. Microvascular endothelial cells increase proliferation and inhibit apoptosis of native human acute myelogenous leukemia blasts. Int J Cancer 2006;119(10): 2313-21
32. Bruserud O, Ryningen A, Wergeland L, et al. Osteoblasts increase proliferation and release of pro-angiogenic interleukin 8 by native human acute myelogenous leukemia blasts. Haematologica 2004;89(4):391-402
33. Bruserud O, Gjertsen BT, Foss B, Huang TS. New strategies in the treatment of acute myelogenous leukemia (AML): in vitro culture of aml cells-the present use in experimental studies and the possible importance for future therapeutic approaches. Stem Cells 2001;19(1):1-11
34. Astori A, Fredly H, Aloysius TA, et al. CXXC5 (retinoid-inducible nuclear factor, RINF) is a potential therapeutic target in high-risk human acute myeloid leukemia. Oncotarget 2013;4(9):1438-48
35. Diffner E, Beck D, Gudgin E, et al. Activity of a heptad of transcription factors is associated with stem cell programs and clinical outcome in acute myeloid leukemia. Blood 2013;121(12):2289-300
36. Valk PJ, Verhaak RG, Beijen MA, et al. Prognostically useful gene-expression profiles in acute myeloid leukemia. N Engl J Med 2004;350(16):1617-28
37. Li Z, Lu J, Sun M, et al. Distinct microRNA expression profiles in acute myeloid leukemia with common translocations. Proc Natl Acad Sci USA 2008; 105(40):15535-40
38. Mardis ER, Ding L, Dooling DJ, et al. Recurring mutations found by sequencing an acute myeloid leukemia genome. N Engl J Med 2009;361(11):1058-66
39. Loken MR, Alonzo TA, Pardo L, et al. Residual disease detected by multidimensional flow cytometry signifies high relapse risk in patients with de novo acute myeloid leukemia: a report from Children's Oncology Group. Blood 2012; 120(8):1581-8
40. Schulze H, Ballmaier M, Welte K, Germeshausen M. Thrombopoietin induces the generation of distinct Stat1, Stat3, Stat5a and Stat5b homo-and heterodimeric complexes with different kinetics in human platelets. Exp Hematol 2000;28(3):294-304
41. Zhang X, Darnell JE, Jr. Functional importance of Stat3 tetramerization in activation of the alpha 2-macroglobulin gene. J Biol Chem 2001;276(36):33576-81
42. Rane SG, Reddy EP. JAKs, STATs and Src kinases in hematopoiesis. Oncogene 2002; 21(21):3334-58
43. Bruserud O, Huang TS, Glenjen N, et al. Leptin in human acute myelogenous leukemia: studies of in vivo levels and in vitro effects on native functional leukemia blasts. Haematologica 2002;87(6): 584-95
44. Foss B, Ulvestad E, Bruserud O. Platelet-derived growth factor (PDGF) in human acute myelogenous leukemia: PDGF receptor expression, endogenous PDGF release and responsiveness to exogenous PDGF isoforms by in vitro cultured acute myelogenous leukemia blasts. Eur J Haematol 2001;66(6):365-76
45. Reich NC, Liu L. Tracking STAT nuclear traffic. Nat Rev Immunol 2006;6(8):602-12
46. Ma J, Zhang T, Novotny-Diermayr V, et al. A novel sequence in the coiled-coil domain of Stat3 essential for its nuclear translocation. J Biol Chem 2003;278(31): 29252-60
47. Ma J, Cao X. Regulation of Stat3 nuclear import by importin alpha5 and importin alpha7 via two different functional sequence elements. Cell Signal 2006;18(8):1117-26
48. Liu L, McBride KM, Reich NC. STAT3 nuclear import is independent of tyrosine phosphorylation and mediated by importin-alpha3. Proc Natl Acad Sci USA 2005;102(23):8150-5
49. Groner B. Determinants of the extent and duration of STAT3 signaling. Jak-Stat 2012; 1(3):211-15
50. Yang J, Liao X, Agarwal MK, et al. Unphosphorylated STAT3 accumulates in response to IL-6 and activates transcription by binding to NFkappaB. Genes Devel 2007;21(11):1396-408
51. Meier JA, Larner AC. Toward a new STATe: the role of STATs in mitochondrial function. Sem Immunol 2014;26(1):20-8
52. Tammineni P, Anugula C, Mohammed F, et al. The import of the transcription factor STAT3 into mitochondria depends on GRIM-19, a component of the electron transport chain. J Biol Chem 2013;288(7): 4723-32
53. Wegrzyn J, Potla R, Chwae YJ, et al. Function of mitochondrial Stat3 in cellular respiration. Science 2009;323(5915):793-7
54. Boengler K, Hilfiker-Kleiner D, Heusch G, Schulz R. Inhibition of permeability transition pore opening by mitochondrial STAT3 and its role in myocardial ischemia/reperfusion. Bas Res Cardiol 2010;105(6): 771-85
55. Boengler K, Ungefug E, Heusch G, Schulz R. The STAT3 inhibitor stattic impairs cardiomyocyte mitochondrial function through increased reactive oxygen species formation. Curr Pharm Des 2013; 19(39):6890-5
56. Shulga N, Pastorino JG. GRIM-19-mediated translocation of STAT3 to mitochondria is necessary for TNF-induced necroptosis. J Cell Sci 2012; 125(Pt 12):2995-3003
57. Wakahara R, Kunimoto H, Tanino K, et al. Phospho-Ser727 of STAT3 regulates STAT3 activity by enhancing dephosphorylation of phospho-Tyr705 largely through TC45. Genes Cells 2012;17(2):132-45
58. Gao SP, Bromberg JF. Touched and moved by STAT3. Sci STKE 2006;2006(343):pe30
59. Zouein FA, Kurdi M, Booz GW. Dancing rhinos in stilettos: the amazing saga of the genomic and nongenomic actions of STAT3 in the heart. Jak-STAT 2013;2(3): e24352
60. Sydor JR, Normant E, Pien CS, et al. Development of 17-allylamino-17-demethoxygeldanamycin hydroquinone hydrochloride (IPI-504), an anti-cancer agent directed against Hsp90. Proc Natl Acad Sci USA 2006;103(46):17408-13
61. Verma NK, Dourlat J, Davies AM, et al. STAT3-stathmin interactions control microtubule dynamics in migrating T-cells. Journal Biol Chem 2009;284(18):12349-62
62. Wei Z, Jiang X, Qiao H, et al. STAT3 interacts with Skp2/p27/p21 pathway to regulate the motility and invasion of gastric cancer cells. Cell Signal 2013;25(4):931-8
63. Bid HK, Oswald D, Li C, et al. Anti-angiogenic activity of a small molecule STAT3 inhibitor LLL12. PLoS One 2012; 7(4):e35513
64. Shen S, Niso-Santano M, Adjemian S, et al. Cytoplasmic STAT3 represses autophagy by inhibiting PKR activity. Mol Cell 2012; 48(5):667-80
65. Xia Z, Baer MR, Block AW, et al. Expression of signal transducers and activators of transcription proteins in acute myeloid leukemia blasts. Cancer Res 1998; 58(14):3173-80
66. Xia Z, Sait SN, Baer MR, et al. Truncated STAT proteins are prevalent at relapse of acute myeloid leukemia. Leuk Res 2001; 25(6):473-82
67. Benekli M, Xia Z, Donohue KA, et al. Constitutive activity of signal transducer and activator of transcription 3 protein in acute myeloid leukemia blasts is associated with short disease-free survival. Blood 2002; 99(1):252-7
68. Pilati C, Amessou M, Bihl MP, et al. Somatic mutations activating STAT3 in human inflammatory hepatocellular adenomas. J Exp Med 2011;208(7):1359-66
69. Koskela HL, Eldfors S, Ellonen P, et al. Somatic STAT3 mutations in large granular lymphocytic leukemia. N Engl J Med 2012; 366(20):1905-13
70. Ghoshal Gupta S, Baumann H, Wetzler M. Epigenetic regulation of signal transducer and activator of transcription 3 in acute myeloid leukemia. Leuk Res 2008;32(7): 1005-14
71. Hankey PA. Regulation of hematopoietic cell development and function by Stat3. Front Biosci 2009;14:5273-90
72. Li HS, Watowich SS. Diversification of dendritic cell subsets: emerging roles for STAT proteins. Jak-Stat 2013;2(4):e25112
73. Laouar Y, Welte T, Fu XY, Flavell RA. STAT3 is required for Flt3L-dependent dendritic cell differentiation. Immunity 2003;19(6):903-12
74. Barton BE. STAT3: a potential therapeutic target in dendritic cells for the induction of transplant tolerance. Expert Opin Ther Targets 2006;10(3):459-70
75. Park SJ, Nakagawa T, Kitamura H, et al. IL-6 regulates in vivo dendritic cell differentiation through STAT3 activation. J Immunol 2004;173(6):3844-54
76. Liu WH, Liu JJ, Wu J, et al. Novel mechanism of inhibition of dendritic cells maturation by mesenchymal stem cells via interleukin-10 and the JAK1/STAT3 signaling pathway. PLoS One 2013; 8(1): e55487
77. Braun DA, Fribourg M, Sealfon SC. Cytokine response is determined by duration of receptor and signal transducers and activators of transcription 3 (STAT3) activation. J Biol Chem 2013;288(5): 2986-93
78. Mandal T, Bhowmik A, Chatterjee A, et al. Reduced phosphorylation of Stat3 at Ser-727 mediated by casein kinase 2-Protein phosphatase 2A enhances Stat3 Tyr-705 induced tumorigenic potential of glioma cells. Cell Signal 2014; 26(8):1725-34
79. Huang G, Yan H, Ye S, et al. STAT3 phosphorylation at tyrosine 705 and serine 727 differentially regulates mouse ESC fates. Stem Cells 2014;32(5):1149-60
80. Miyakoshi M, Yamamoto M, Tanaka H, Ogawa K. Serine 727 phosphorylation of STAT3: an early change in mouse hepatocarcinogenesis induced by neonatal treatment with diethylnitrosamine. Mol Carcinogen 2014;53(1):67-76
81. Snyder M, Huang J, Huang XY, Zhang JJ. A STAT3/NFkappaB Complex is Necessary for the Expression of Fascin in Metastatic Breast Cancer Cells in Response to IL-6 and TNF-alpha. Jl Biol Chemi 2014
82. Choi Y, Kim JK, Yoo JY. NFkappaB and STAT3 synergistically activate the expression of FAT10, a gene counteracting the tumor suppressor p53. Mol Oncol 2014;8(3): 642-55
83. Wieczorek M, Ginter T, Brand P, et al. Acetylation modulates the STAT signaling code. Cytokine Growth Factor Rev 2012; 23(6):293-305
84. Qi QR, Yang ZM. Regulation and function of signal transducer and activator of transcription 3. World J Biol Chemi 2014; 5(2):231-9
85. Zhuang S. Regulation of STAT signaling by acetylation. Cell Signal 2013;25(9):1924-31
86. Yuan ZL, Guan YJ, Chatterjee D, Chin YE. Stat3 dimerization regulated by reversible acetylation of a single lysine residue. Science 2005;307(5707):269-73
87. Lee CK, Raz R, Gimeno R, et al. STAT3 is a negative regulator of granulopoiesis but is not required for G-CSF-dependent differentiation. Immunity 2002;17(1):63-72
88. Welte T, Zhang SS, Wang T, et al. STAT3 deletion during hematopoiesis causes Crohn's disease-like pathogenesis and lethality: a critical role of STAT3 in innate immunity. Proc Natl Acad Sci USA 2003; 100(4):1879-84
89. Chung YJ, Park BB, Kang YJ, et al. Unique effects of Stat3 on the early phase of hematopoietic stem cell regeneration. Blood 2006;108(4):1208-15
90. Ridinger-Saison M, Boeva V, Rimmele P, et al. Spi-1/PU.1 activates transcription through clustered DNA occupancy in erythroleukemia. Nucleic Acids Res 2012; 40(18):8927-41
91. Basova P, Pospisil V, Savvulidi F, et al. Aggressive acute myeloid leukemia in PU.1/p53 double-mutant mice. Oncogene 2014; 33(39):4735-45
92. Hegde S, Ni S, He S, et al. Stat3 promotes the development of erythroleukemia by inducing Pu.1 expression and inhibiting erythroid differentiation. Oncogene 2009; 28(38):3349-59
93. Terui Y, Ogura M, Uchida T, et al. Phase I study of OPB-51602, an inhibitor of STAT3 phosphorylation in patients with relapsed/refractory hematological malignancies. Haematologica 2014;30: abstract 185
94. Souissi I, Najjar I, Ah-Koon L, et al. A STAT3-decoy oligonucleotide induces cell death in a human colorectal carcinoma cell line by blocking nuclear transfer of STAT3 and STAT3-bound NF-kappaB. BMC Cell Biol 2011;12:14
95. Lui VW, Boehm AL, Koppikar P, et al. Antiproliferative mechanisms of a transcription factor decoy targeting signal transducer and activator of transcription (STAT) 3: the role of STAT1. Mol Pharmacol 2007;71(5):1435-43
96. Seavey MM, Dobrzanski P. The many faces of Janus kinase. Biochem Pharmacol 2012; 83(9):1136-45
97. Rozovski U, Wu JY, Harris DM, et al. Stimulation of the B-cell receptor activates the JAK2/STAT3 signaling pathway in chronic lymphocytic leukemia cells. Blood 2014;123(24):3797-802
98. Looyenga BD, Hutchings D, Cherni I, et al. STAT3 is activated by JAK2 independent of key oncogenic driver mutations in non-small cell lung carcinoma. PLoS One 2012;7(2):e30820
99. Eghtedar A, Verstovsek S, Estrov Z, et al. Phase 2 study of the JAK kinase inhibitor ruxolitinib in patients with refractory leukemias, including postmyeloproliferative neoplasm acute myeloid leukemia. Blood 2012;119(20):4614-18
100. Yang H, Lawrence HR, Kazi A, et al. Dual Aurora A and JAK2 kinase blockade effectively suppresses malignant transformation. Oncotarget 2014;5(10): 2947-61
101. Mantel C, Messina-Graham S, Moh A, et al. Mouse hematopoietic cell-targeted STAT3 deletion: stem/progenitor cell defects, mitochondrial dysfunction, ROS overproduction, and a rapid aging-like phenotype. Blood 2012;120(13):2589-99
102. Gao X, Wang H, Yang JJ, et al. Pyruvate kinase M2 regulates gene transcription by acting as a protein kinase. Mol Cell 2012; 45(5):598-609
103. Demaria M, Giorgi C, Lebiedzinska M, et al. A STAT3-mediated metabolic switch is involved in tumour transformation and STAT3 addiction. Aging 2010;2(11):823-42
104. Pelicano H, Martin DS, Xu RH, Huang P. Glycolysis inhibition for anticancer treatment. Oncogene 2006;25(34):4633-46
105. Herst PM, Howman RA, Neeson PJ, et al. The level of glycolytic metabolism in acute myeloid leukemia blasts at diagnosis is prognostic for clinical outcome. J Leukoc Biol 2011;89(1):51-5
106. Talekar M, Boreddy SR, Singh A, Amiji M. Tumor aerobic glycolysis: new insights into therapeutic strategies with targeted delivery. Expert Opin Biol Ther 2014;14(8): 1145-59
107. Lagadinou ED, Sach A, Callahan K, et al. BCL-2 inhibition targets oxidative phosphorylation and selectively eradicates quiescent human leukemia stem cells. Cell Stem Cell 2013;12(3):329-41
108. Gao X, Wang H, Yang JJ, et al. Reciprocal regulation of protein kinase and pyruvate kinase activities of pyruvate kinase M2 by growth signals. J Biol Chem 2013;288(22): 15971-9
109. Hossain DM, Dos Santos C, Zhang Q, et al. Leukemia cell-targeted STAT3 silencing and TLR9 triggering generate systemic antitumor immunity. Blood 2014;123(1):15-25