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Anti-Cancer Agents in Medicinal Chemistry

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ISSN (Print): 1871-5206
ISSN (Online): 1875-5992

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Review Article

STAT5 and STAT5 Inhibitors in Hematological Malignancies

Author(s): Manlio Tolomeo*, Maria Meli and Stefania Grimaudo

Volume 19, Issue 17, 2019

Page: [2036 - 2046] Pages: 11

DOI: 10.2174/1871520619666190906160848

Price: $65

Abstract

The JAK-STAT pathway is an important physiologic regulator of different cellular functions including proliferation, apoptosis, differentiation, and immunological responses. Out of six different STAT proteins, STAT5 plays its main role in hematopoiesis and constitutive STAT5 activation seems to be a key event in the pathogenesis of several hematological malignancies. This has led many researchers to develop compounds capable of inhibiting STAT5 activation or interfering with its functions. Several anti-STAT5 molecules have shown potent STAT5 inhibitory activity in vitro. However, compared to the large amount of clinical studies with JAK inhibitors that are currently widely used in the clinics to treat myeloproliferative disorders, the clinical trials with STAT5 inhibitors are very limited. At present, a few STAT5 inhibitors are in phase I or II clinical trials for the treatment of leukemias and graft vs host disease. These studies seem to indicate that such compounds could be well tolerated and useful in reducing the occurrence of resistance to tyrosine kinase inhibitors in chronic myeloid leukemia. Of interest, STAT5 seems to play an important role in the regulation of hematopoietic stem cell self-renewal suggesting that combination therapies including STAT5 inhibitors can erode the cancer stem cell pool and possibly open the way for the complete cancer eradication. In this review, we discuss the implication of STAT5 in hematological malignancies and the results obtained with the novel STAT5 inhibitors.

Keywords: STAT transcription factors, STAT5 inhibitors, leukemia, BCR-ABL, FLT3-ITD, Jak2V617F.

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[1]
Fu, X.Y.; Schindler, C.; Improta, T.; Aebersold, R.; Darnell, J.E., Jr The proteins of ISGF-3, the interferon alpha-induced transcriptional activator, define a gene family involved in signal transduction. Proc. Natl. Acad. Sci. USA, 1992, 89(16), 7840-7843.
[http://dx.doi.org/10.1073/pnas.89.16.7840] [PMID: 1502204]
[2]
Schindler, C.; Fu, X.Y.; Improta, T.; Aebersold, R.; Darnell, J.E., Jr Proteins of transcription factor ISGF-3: One gene encodes the 91-and 84-kDa ISGF-3 proteins that are activated by interferon alpha. Proc. Natl. Acad. Sci. USA, 1992, 89(16), 7836-7839.
[http://dx.doi.org/10.1073/pnas.89.16.7836] [PMID: 1502203]
[3]
Schindler, C.; Shuai, K.; Prezioso, V.R.; Darnell, J.E., Jr Interferon-dependent tyrosine phosphorylation of a latent cytoplasmic transcription factor. Science, 1992, 257(5071), 809-813.
[http://dx.doi.org/10.1126/science.1496401] [PMID: 1496401]
[4]
Chatterjee-Kishore, M.; van den Akker, F.; Stark, G.R. Association of STATs with relatives and friends. Trends Cell Biol., 2000, 10(3), 106-111.
[http://dx.doi.org/10.1016/S0962-8924(99)01709-2] [PMID: 10675904]
[5]
Abroun, S.; Saki, N.; Ahmadvand, M.; Asghari, F.; Salari, F.; Rahim, F. STATs: An old story, yet mesmerizing. Cell J., 2015, 17(3), 395-411.
[PMID: 26464811]
[6]
Ferbeyre, G.; Moriggl, R. The role of Stat5 transcription factors as tumor suppressors or oncogenes. Biochim. Biophys. Acta, 2011, 1815(1), 104-114.
[PMID: 20969928]
[7]
Lim, C.P.; Cao, X. Structure, function, and regulation of STAT proteins. Mol. Biosyst., 2006, 2(11), 536-550.
[http://dx.doi.org/10.1039/b606246f] [PMID: 17216035]
[8]
Ehret, G.B.; Reichenbach, P.; Schindler, U.; Horvath, C.M.; Fritz, S.; Nabholz, M.; Bucher, P. DNA binding specificity of different STAT proteins. Comparison of in vitro specificity with natural target sites. J. Biol. Chem., 2001, 276(9), 6675-6688.
[http://dx.doi.org/10.1074/jbc.M001748200] [PMID: 11053426]
[9]
Ihle, J.N. The Janus kinase family and signaling through members of the cytokine receptor superfamily. Proc. Soc. Exp. Biol. Med., 1994, 206(3), 268-272.
[http://dx.doi.org/10.3181/00379727-206-43757] [PMID: 7517047]
[10]
Darnell, J.E., Jr; Kerr, I.M.; Stark, G.R. Jak-STAT pathways and transcriptional activation in response to IFNs and other extracellular signaling proteins. Science, 1994, 264(5164), 1415-1421.
[http://dx.doi.org/10.1126/science.8197455] [PMID: 8197455]
[11]
Yamaoka, K.; Saharinen, P.; Pesu, M.; Holt, V.E.T., III; Silvennoinen, O.; O’Shea, J.J. The Janus kinases (Jaks). Genome Biol., 2004, 5(12), 253.
[http://dx.doi.org/10.1186/gb-2004-5-12-253] [PMID: 15575979]
[12]
Wang, X.; Lupardus, P.; Laporte, S.L.; Garcia, K.C. Structural biology of shared cytokine receptors. Annu. Rev. Immunol., 2009, 27(1), 29-60.
[http://dx.doi.org/10.1146/annurev.immunol.24.021605.090616] [PMID: 18817510]
[13]
Jatiani, S.S.; Baker, S.J.; Silverman, L.R.; Reddy, E.P. Jak/STAT pathways in cytokine signaling and myeloproliferative disorders: Approaches for targeted therapies. Genes Cancer, 2010, 1(10), 979-993.
[http://dx.doi.org/10.1177/1947601910397187] [PMID: 21442038]
[14]
Shuai, K.; Horvath, C.M.; Huang, L.H.; Qureshi, S.A.; Cowburn, D.; Darnell, J.E., Jr Interferon activation of the transcription factor Stat91 involves dimerization through SH2-phosphotyrosyl peptide interactions. Cell, 1994, 76(5), 821-828.
[http://dx.doi.org/10.1016/0092-8674(94)90357-3] [PMID: 7510216]
[15]
Novak, U.; Ji, H.; Kanagasundaram, V.; Simpson, R.; Paradiso, L. STAT3 forms stable homodimers in the presence of divalent cations prior to activation. Biochem. Biophys. Res. Commun., 1998, 247(3), 558-563.
[http://dx.doi.org/10.1006/bbrc.1998.8829] [PMID: 9647732]
[16]
Wingelhofer, B.; Neubauer, H.A.; Valent, P.; Han, X.; Constantinescu, S.N.; Gunning, P.T.; Müller, M.; Moriggl, R. Implications of STAT3 and STAT5 signaling on gene regulation and chromatin remodeling in hematopoietic cancer. Leukemia, 2018, 32(8), 1713-1726.
[http://dx.doi.org/10.1038/s41375-018-0117-x] [PMID: 29728695]
[17]
Thomas, S.J.; Snowden, J.A.; Zeidler, M.P.; Danson, S.J. The role of JAK/STAT signalling in the pathogenesis, prognosis and treatment of solid tumours. Br. J. Cancer, 2015, 113(3), 365-371.
[http://dx.doi.org/10.1038/bjc.2015.233] [PMID: 26151455]
[18]
Pencik, J.; Pham, H.T.T.; Schmoellerl, J.; Javaheri, T.; Schlederer, M.; Culig, Z.; Merkel, O.; Moriggl, R.; Grebien, F.; Kenner, L. JAK-STAT signaling in cancer: From cytokines to non-coding genome. Cytokine, 2016, 87, 26-36.
[http://dx.doi.org/10.1016/j.cyto.2016.06.017] [PMID: 27349799]
[19]
Groner, B.; von Manstein, V. Jak Stat signaling and cancer: Opportunities, benefits and side effects of targeted inhibition. Mol. Cell. Endocrinol., 2017, 451, 1-14.
[http://dx.doi.org/10.1016/j.mce.2017.05.033] [PMID: 28576744]
[20]
Warsch, W.; Walz, C.; Sexl, V. JAK of all trades: JAK2-STAT5 as novel therapeutic targets in BCR-ABL1+ chronic myeloid leukemia. Blood, 2013, 122(13), 2167-2175.
[http://dx.doi.org/10.1182/blood-2013-02-485573] [PMID: 23926299]
[21]
Brady, A.; Gibson, S.; Rybicki, L.; Hsi, E.; Saunthararajah, Y.; Sekeres, M.A.; Tiu, R.; Copelan, E.; Kalaycio, M.; Sobecks, R.; Bates, J.; Advani, A.S. Expression of phosphorylated signal transducer and activator of transcription 5 is associated with an increased risk of death in acute myeloid leukemia. Eur. J. Haematol., 2012, 89(4), 288-293.
[http://dx.doi.org/10.1111/j.1600-0609.2012.01825.x] [PMID: 22725130]
[22]
Schmitt-Ney, M.; Doppler, W.; Ball, R.K.; Groner, B. Beta-casein gene promoter activity is regulated by the hormone-mediated relief of transcriptional repression and a mammary-gland-specific nuclear factor. Mol. Cell. Biol., 1991, 11(7), 3745-3755.
[http://dx.doi.org/10.1128/MCB.11.7.3745] [PMID: 2046676]
[23]
Hennighausen, L.; Robinson, G.W. Interpretation of cytokine signaling through the transcription factors STAT5A and STAT5B. Genes Dev., 2008, 22(6), 711-721.
[http://dx.doi.org/10.1101/gad.1643908] [PMID: 18347089]
[24]
Oshida, K.; Vasani, N.; Waxman, D.J.; Corton, J.C. Disruption of STAT5b-regulated sexual dimorphism of the liver transcriptome by diverse factors is a common event. PLoS One, 2016, 11(3)e0148308
[http://dx.doi.org/10.1371/journal.pone.0148308] [PMID: 26959975]
[25]
Liu, X.; Gallego, M.I.; Smith, G.H.; Robinson, G.W.; Hennighausen, L. Functional rescue of Stat5a-null mammary tissue through the activation of compensating signals including Stat5b. Cell Growth Differ., 1998, 9(9), 795-803.
[PMID: 9751123]
[26]
Hoelbl, A.; Kovacic, B.; Kerenyi, M.A.; Simma, O.; Warsch, W.; Cui, Y.; Beug, H.; Hennighausen, L.; Moriggl, R.; Sexl, V. Clarifying the role of Stat5 in lymphoid development and Abelson-induced transformation. Blood, 2006, 107(12), 4898-4906.
[http://dx.doi.org/10.1182/blood-2005-09-3596] [PMID: 16493008]
[27]
Lee, J.; Seong, S.; Kim, J.H.; Kim, K.; Kim, I.; Jeong, B-C.; Nam, K-I.; Kim, K.K.; Hennighausen, L.; Kim, N. STAT5 is a key transcription factor for IL-3-mediated inhibition of RANKL-induced osteoclastogenesis. Sci. Rep., 2016, 6(1), 30977.
[http://dx.doi.org/10.1038/srep30977] [PMID: 27485735]
[28]
Wan, C-K.; Oh, J.; Li, P.; West, E.E.; Wong, E.A.; Andraski, A.B.; Spolski, R.; Yu, Z-X.; He, J.; Kelsall, B.L.; Leonard, W.J. The cytokines IL-21 and GM-CSF have opposing regulatory roles in the apoptosis of conventional dendritic cells. Immunity, 2013, 38(3), 514-527.
[http://dx.doi.org/10.1016/j.immuni.2013.02.011] [PMID: 23453633]
[29]
Iavnilovitch, E.; Cardiff, R.D.; Groner, B.; Barash, I. Deregulation of Stat5 expression and activation causes mammary tumors in transgenic mice. Int. J. Cancer, 2004, 112(4), 607-619.
[http://dx.doi.org/10.1002/ijc.20484] [PMID: 15382041]
[30]
Stewart, W.C.; Pearcy, L.A.; Floyd, Z.E.; Stephens, J.M. STAT5A expression in Swiss 3T3 cells promotes adipogenesis in vivo in an athymic mice model system. Obesity (Silver Spring), 2011, 19(9), 1731-1734.
[http://dx.doi.org/10.1038/oby.2011.66] [PMID: 21494231]
[31]
Gao, P.; Zhang, Y.; Liu, Y.; Chen, J.; Zong, C.; Yu, C.; Cui, S.; Gao, W.; Qin, D.; Sun, W.; Li, X.; Wang, X. Signal transducer and activator of transcription 5B (STAT5B) modulates adipocyte differentiation via MOF. Cell. Signal., 2015, 27(12), 2434-2443.
[http://dx.doi.org/10.1016/j.cellsig.2015.09.010] [PMID: 26388045]
[32]
Paukku, K.; Silvennoinen, O. STATs as critical mediators of signal transduction and transcription: Lessons learned from STAT5. Cytokine Growth Factor Rev., 2004, 15(6), 435-455.
[http://dx.doi.org/10.1016/j.cytogfr.2004.09.001] [PMID: 15561601]
[33]
Bunting, K.D. STAT5 signaling in normal and pathologic hematopoiesis. Front. Biosci., 2007, 12, 2807-2820.
[http://dx.doi.org/10.2741/2274] [PMID: 17485261]
[34]
Pallard, C.; Gouilleux, F.; Charon, M.; Groner, B.; Gisselbrecht, S.; Dusanter-Fourt, I. Interleukin-3, erythropoietin, and prolactin activate a STAT5-like factor in lymphoid cells. J. Biol. Chem., 1995, 270(27), 15942-15945.
[http://dx.doi.org/10.1074/jbc.270.27.15942] [PMID: 7608147]
[35]
Schindler, C.; Darnell, J.E., Jr Transcriptional responses to polypeptide ligands: The JAK-STAT pathway. Annu. Rev. Biochem., 1995, 64(1), 621-651.
[http://dx.doi.org/10.1146/annurev.bi.64.070195.003201] [PMID: 7574495]
[36]
Feugier, P.; Li, N.; Jo, D.Y.; Shieh, J.H.; MacKenzie, K.L.; Lesesve, J.F.; Latger-Cannard, V.; Bensoussan, D.; Crystal, R.G.; Rafii, S.; Stoltz, J.F.; Moore, M.A. Osteopetrotic mouse stroma with thrombopoietin, c-kit ligand, and flk-2 ligand supports long-term mobilized CD34+ hematopoiesis in vitro. Stem Cells Dev., 2005, 14(5), 505-516.
[http://dx.doi.org/10.1089/scd.2005.14.505] [PMID: 16305336]
[37]
Bunting, K.D.; Bradley, H.L.; Hawley, T.S.; Moriggl, R.; Sorrentino, B.P.; Ihle, J.N. Reduced lymphomyeloid repopulating activity from adult bone marrow and fetal liver of mice lacking expression of STAT5. Blood, 2002, 99(2), 479-487.
[http://dx.doi.org/10.1182/blood.V99.2.479] [PMID: 11781228]
[38]
Wang, Z.; Li, G.; Tse, W.; Bunting, K.D. Conditional deletion of STAT5 in adult mouse hematopoietic stem cells causes loss of quiescence and permits efficient nonablative stem cell replacement. Blood, 2009, 113(20), 4856-4865.
[http://dx.doi.org/10.1182/blood-2008-09-181107] [PMID: 19258595]
[39]
Ye, D.; Wolff, N.; Li, L.; Zhang, S.; Ilaria, R.L., Jr STAT5 signaling is required for the efficient induction and maintenance of CML in mice. Blood, 2006, 107(12), 4917-4925.
[http://dx.doi.org/10.1182/blood-2005-10-4110] [PMID: 16522816]
[40]
Nieborowska-Skorska, M.; Wasik, M.A.; Slupianek, A.; Salomoni, P.; Kitamura, T.; Calabretta, B.; Skorski, T. Signal transducer and activator of transcription (STAT)5 activation by BCR/ABL is dependent on intact Src homology (SH)3 and SH2 domains of BCR/ABL and is required for leukemogenesis. J. Exp. Med., 1999, 189(8), 1229-1242.
[http://dx.doi.org/10.1084/jem.189.8.1229] [PMID: 10209040]
[41]
Hoelbl, A.; Schuster, C.; Kovacic, B.; Zhu, B.; Wickre, M.; Hoelzl, M.A.; Fajmann, S.; Grebien, F.; Warsch, W.; Stengl, G.; Hennighausen, L.; Poli, V.; Beug, H.; Moriggl, R.; Sexl, V. Stat5 is indispensable for the maintenance of bcr/abl-positive leukaemia. EMBO Mol. Med., 2010, 2(3), 98-110.
[http://dx.doi.org/10.1002/emmm.201000062] [PMID: 20201032]
[42]
Birkenkamp, K.U.; Geugien, M.; Lemmink, H.H.; Kruijer, W.; Vellenga, E. Regulation of constitutive STAT5 phosphorylation in acute myeloid leukemia blasts. Leukemia, 2001, 15(12), 1923-1931.
[http://dx.doi.org/10.1038/sj.leu.2402317] [PMID: 11753614]
[43]
Gouilleux-Gruart, V.; Gouilleux, F.; Desaint, C.; Claisse, J.F.; Capiod, J.C.; Delobel, J.; Weber-Nordt, R.; Dusanter-Fourt, I.; Dreyfus, F.; Groner, B.; Prin, L. STAT-related transcription factors are constitutively activated in peripheral blood cells from acute leukemia patients. Blood, 1996, 87(5), 1692-1697.
[PMID: 8634413]
[44]
Spiekermann, K.; Pau, M.; Schwab, R.; Schmieja, K.; Franzrahe, S.; Hiddemann, W. Constitutive activation of STAT3 and STAT5 is induced by leukemic fusion proteins with protein tyrosine kinase activity and is sufficient for transformation of hematopoietic precursor cells. Exp. Hematol., 2002, 30(3), 262-271.
[http://dx.doi.org/10.1016/S0301-472X(01)00787-1] [PMID: 11882364]
[45]
Lacout, C.; Pisani, D.F.; Tulliez, M.; Gachelin, F.M.; Vainchenker, W.; Villeval, J-L. JAK2V617F expression in murine hematopoietic cells leads to MPD mimicking human PV with secondary myelofibrosis. Blood, 2006, 108(5), 1652-1660.
[http://dx.doi.org/10.1182/blood-2006-02-002030] [PMID: 16670266]
[46]
Wernig, G.; Mercher, T.; Okabe, R.; Levine, R.L.; Lee, B.H.; Gilliland, D.G. Expression of Jak2V617F causes a polycythemia vera-like disease with associated myelofibrosis in a murine bone marrow transplant model. Blood, 2006, 107(11), 4274-4281.
[http://dx.doi.org/10.1182/blood-2005-12-4824] [PMID: 16478879]
[47]
Simpson, H.M.; Furusawa, A.; Sadashivaiah, K.; Civin, C.I.; Banerjee, A. STAT5 inhibition induces TRAIL/DR4 dependent apoptosis in peripheral T-cell lymphoma. Oncotarget, 2018, 9(24), 16792-16806.
[http://dx.doi.org/10.18632/oncotarget.24698] [PMID: 29682185]
[48]
Gesbert, F.; Griffin, J.D. Bcr/Abl activates transcription of the Bcl-X gene through STAT5. Blood, 2000, 96(6), 2269-2276.
[PMID: 10979976]
[49]
Magné, S.; Caron, S.; Charon, M.; Rouyez, M-C.; Dusanter-Fourt, I. STAT5 and Oct-1 form a stable complex that modulates cyclin D1 expression. Mol. Cell. Biol., 2003, 23(24), 8934-8945.
[http://dx.doi.org/10.1128/MCB.23.24.8934-8945.2003] [PMID: 14645506]
[50]
de Groot, R.P.; Raaijmakers, J.A.M.; Lammers, J-W.J.; Koenderman, L. STAT5-dependent cyclinD1 and Bcl-XL expression in Bcr-Abl-transformed cells. Mol. Cell Biol. Res. Commun., 2000, 3(5), 299-305.
[http://dx.doi.org/10.1006/mcbr.2000.0231] [PMID: 10964754]
[51]
Ross, T.S.; Mgbemena, V.E. Re-evaluating the role of BCR/ABL in chronic myelogenous leukemia. Mol. Cell. Oncol., 2014, 1(3)e963450
[http://dx.doi.org/10.4161/23723548.2014.963450] [PMID: 27308345]
[52]
Salesse, S.; Verfaillie, C.M. BCR/ABL: From molecular mechanisms of leukemia induction to treatment of chronic myelogenous leukemia. Oncogene, 2002, 21(56), 8547-8559.
[http://dx.doi.org/10.1038/sj.onc.1206082] [PMID: 12476301]
[53]
Cuellar, S.; Vozniak, M.; Rhodes, J.; Forcello, N.; Olszta, D. BCR-ABL1 tyrosine kinase inhibitors for the treatment of chronic myeloid leukemia. J. Oncol. Pharm. Pract., 2018, 24(6), 433-452.
[http://dx.doi.org/10.1177/1078155217710553] [PMID: 28580869]
[54]
Massaro, F.; Colafigli, G.; Molica, M.; Breccia, M. Novel tyrosine-kinase inhibitors for the treatment of chronic myeloid leukemia: Safety and efficacy. Expert Rev. Hematol., 2018, 11(4), 301-306.
[http://dx.doi.org/10.1080/17474086.2018.1451322] [PMID: 29522367]
[55]
Saglio, G.; Jabbour, E. First-line therapy for chronic phase CML: Selecting the optimal BCR-ABL1-targeted TKI. Leuk. Lymphoma, 2018, 59(7), 1523-1538.
[http://dx.doi.org/10.1080/10428194.2017.1379074] [PMID: 28972424]
[56]
Inoue, A.; Kobayashi, C.I.; Shinohara, H.; Miyamoto, K.; Yamauchi, N.; Yuda, J.; Akao, Y.; Minami, Y. Chronic myeloid leukemia stem cells and molecular target therapies for overcoming resistance and disease persistence. Int. J. Hematol., 2018, 108(4), 365-370.
[http://dx.doi.org/10.1007/s12185-018-2519-y] [PMID: 30155588]
[57]
Talati, C.; Pinilla-Ibarz, J. Resistance in chronic myeloid leukemia: Definitions and novel therapeutic agents. Curr. Opin. Hematol., 2018, 25(2), 154-161.
[PMID: 29266016]
[58]
Warsch, W.; Grundschober, E.; Sexl, V. Adding a new facet to STAT5 in CML: Multitasking for leukemic cells. Cell Cycle, 2013, 12(12), 1813-1814.
[http://dx.doi.org/10.4161/cc.25116] [PMID: 23708512]
[59]
Ilaria, R.L., Jr; Van Etten, R.A. P210 and P190(BCR/ABL) induce the tyrosine phosphorylation and DNA binding activity of multiple specific STAT family members. J. Biol. Chem., 1996, 271(49), 31704-31710.
[http://dx.doi.org/10.1074/jbc.271.49.31704] [PMID: 8940193]
[60]
Carlesso, N.; Frank, D.A.; Griffin, J.D. Tyrosyl phosphorylation and DNA binding activity of signal transducers and activators of transcription (STAT) proteins in hematopoietic cell lines transformed by Bcr/Abl. J. Exp. Med., 1996, 183(3), 811-820.
[http://dx.doi.org/10.1084/jem.183.3.811] [PMID: 8642285]
[61]
Frank, D.A.; Varticovski, L. BCR/abl leads to the constitutive activation of Stat proteins, and shares an epitope with tyrosine phosphorylated Stats. Leukemia, 1996, 10(11), 1724-1730.
[PMID: 8892675]
[62]
Shuai, K.; Halpern, J.; ten Hoeve, J.; Rao, X.; Sawyers, C.L. Constitutive activation of STAT5 by the BCR-ABL oncogene in chronic myelogenous leukemia. Oncogene, 1996, 13(2), 247-254.
[PMID: 8710363]
[63]
Kaymaz, B.T.; Selvi, N.; Gokbulut, A.A.; Aktan, C.; Gündüz, C.; Saydam, G.; Sahin, F.; Cetintaş, V.B.; Baran, Y.; Kosova, B. Suppression of STAT5A and STAT5B chronic myeloid leukemia cells via siRNA and antisense-oligonucleotide applications with the induction of apoptosis. Am. J. Blood Res., 2013, 3(1), 58-70.
[PMID: 23358828]
[64]
Kosova, B.; Tezcanli, B.; Ekiz, H.A.; Cakir, Z.; Selvi, N.; Dalmizrak, A.; Kartal, M.; Gunduz, U.; Baran, Y. Suppression of STAT5A increases chemotherapeutic sensitivity in imatinib-resistant and imatinib-sensitive K562 cells. Leuk. Lymphoma, 2010, 51(10), 1895-1901.
[http://dx.doi.org/10.3109/10428194.2010.507830] [PMID: 20849385]
[65]
Warsch, W.; Kollmann, K.; Eckelhart, E.; Fajmann, S.; Cerny-Reiterer, S.; Hölbl, A.; Gleixner, K.V.; Dworzak, M.; Mayerhofer, M.; Hoermann, G.; Herrmann, H.; Sillaber, C.; Egger, G.; Valent, P.; Moriggl, R.; Sexl, V. High STAT5 levels mediate imatinib resistance and indicate disease progression in chronic myeloid leukemia. Blood, 2011, 117(12), 3409-3420.
[http://dx.doi.org/10.1182/blood-2009-10-248211] [PMID: 21220747]
[66]
Papaemmanuil, E.; Gerstung, M.; Bullinger, L.; Gaidzik, V.I.; Paschka, P.; Roberts, N.D.; Potter, N.E.; Heuser, M.; Thol, F.; Bolli, N.; Gundem, G.; Van Loo, P.; Martincorena, I.; Ganly, P.; Mudie, L.; McLaren, S.; O’Meara, S.; Raine, K.; Jones, D.R.; Teague, J.W.; Butler, A.P.; Greaves, M.F.; Ganser, A.; Döhner, K.; Schlenk, R.F.; Döhner, H.; Campbell, P.J. Genomic classification and prognosis in acute myeloid leukemia. N. Engl. J. Med., 2016, 374(23), 2209-2221.
[http://dx.doi.org/10.1056/NEJMoa1516192] [PMID: 27276561]
[67]
Choudhary, C.; Müller-Tidow, C.; Berdel, W.E.; Serve, H. Signal transduction of oncogenic Flt3. Int. J. Hematol., 2005, 82(2), 93-99.
[http://dx.doi.org/10.1532/IJH97.05090] [PMID: 16146838]
[68]
Schmidt-Arras, D.; Schwäble, J.; Böhmer, F.D.; Serve, H. Flt3 receptor tyrosine kinase as a drug target in leukemia. Curr. Pharm. Des., 2004, 10(16), 1867-1883.
[http://dx.doi.org/10.2174/1381612043384394] [PMID: 15180525]
[69]
Fischer, M.; Schnetzke, U.; Spies-Weisshart, B.; Walther, M.; Fleischmann, M.; Hilgendorf, I.; Hochhaus, A.; Scholl, S. Impact of FLT3-ITD diversity on response to induction chemotherapy in patients with acute myeloid leukemia. Haematologica, 2017, 102(4), e129-e131.
[http://dx.doi.org/10.3324/haematol.2016.157180] [PMID: 28034991]
[70]
Gilliland, D.G.; Griffin, J.D. The roles of FLT3 in hematopoiesis and leukemia. Blood, 2002, 100(5), 1532-1542.
[http://dx.doi.org/10.1182/blood-2002-02-0492] [PMID: 12176867]
[71]
Heng, H.; Wang, Z.; Li, H.; Huang, Y.; Lan, Q.; Guo, X.; Zhang, L.; Zhi, Y.; Cai, J.; Qin, T.; Xiang, L.; Wang, S.; Chen, Y.; Lu, T.; Lu, S. Combining structure- and property-based optimization to identify selective FLT3-ITD inhibitors with good antitumor efficacy in AML cell inoculated mouse xenograft model. Eur. J. Med. Chem., 2019, 176(176), 248-267.
[http://dx.doi.org/10.1016/j.ejmech.2019.05.021] [PMID: 31103903]
[72]
Sutamtewagul, G.; Vigil, C.E. Clinical use of FLT3 inhibitors in acute myeloid leukemia. OncoTargets Ther., 2018, 11(1), 7041-7052.
[http://dx.doi.org/10.2147/OTT.S171640] [PMID: 30410361]
[73]
Mullally, A. Underlying mechanisms of the JAK2V617F mutation in the pathogenesis of myeloproliferative neoplasms. Pathologe, 2016, 37(Suppl. 2), 175-179.
[http://dx.doi.org/10.1007/s00292-016-0240-2] [PMID: 27796499]
[74]
Levine, R.L.; Wadleigh, M.; Cools, J.; Ebert, B.L.; Wernig, G.; Huntly, B.J.P.; Boggon, T.J.; Wlodarska, I.; Clark, J.J.; Moore, S.; Adelsperger, J.; Koo, S.; Lee, J.C.; Gabriel, S.; Mercher, T.; D’Andrea, A.; Fröhling, S.; Döhner, K.; Marynen, P.; Vandenberghe, P.; Mesa, R.A.; Tefferi, A.; Griffin, J.D.; Eck, M.J.; Sellers, W.R.; Meyerson, M.; Golub, T.R.; Lee, S.J.; Gilliland, D.G. Activating mutation in the tyrosine kinase JAK2 in polycythemia vera, essential thrombocythemia, and myeloid metaplasia with myelofibrosis. Cancer Cell, 2005, 7(4), 387-397.
[http://dx.doi.org/10.1016/j.ccr.2005.03.023] [PMID: 15837627]
[75]
Grinfeld, J.; Godfrey, A.L. After 10years of JAK2V617F: Disease biology and current management strategies in polycythaemia vera. Blood Rev., 2017, 31(3), 101-118.
[http://dx.doi.org/10.1016/j.blre.2016.11.001] [PMID: 27884555]
[76]
Saki, N.; Shirzad, R.; Rahim, F.; Saki Malehi, A. Estimation of diagnosis and prognosis in ET by assessment of CALR and JAK2V617F mutations and laboratory findings: A meta-analysis. Clin. Transl. Oncol., 2017, 19(7), 874-883.
[http://dx.doi.org/10.1007/s12094-017-1618-1] [PMID: 28205126]
[77]
Baxter, E.J.; Scott, L.M.; Campbell, P.J.; East, C.; Fourouclas, N.; Swanton, S.; Vassiliou, G.S.; Bench, A.J.; Boyd, E.M.; Curtin, N.; Scott, M.A.; Erber, W.N.; Green, A.R. Cancer Genome Project. Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders. Lancet, 2005, 365(9464), 1054-1061.
[http://dx.doi.org/10.1016/S0140-6736(05)71142-9] [PMID: 15781101]
[78]
Yan, D.; Hutchison, R.E.; Mohi, G. Critical requirement for Stat5 in a mouse model of polycythemia vera. Blood, 2012, 119(15), 3539-3549.
[http://dx.doi.org/10.1182/blood-2011-03-345215] [PMID: 22144185]
[79]
Sonkin, D.; Palmer, M.; Rong, X.; Horrigan, K.; Regnier, C.H.; Fanton, C.; Holash, J.; Pinzon-Ortiz, M.; Squires, M.; Sirulnik, A.; Radimerski, T.; Schlegel, R.; Morrissey, M.; Cao, Z.A. The identification and characterization of a STAT5 gene signature in hematologic malignancies. Cancer Biomark., 2015, 15(1), 79-87.
[http://dx.doi.org/10.3233/CBM-140434] [PMID: 25524945]
[80]
Holyoake, T.L.; Vetrie, D. The chronic myeloid leukemia stem cell: stemming the tide of persistence. Blood, 2017, 129(12), 1595-1606.
[http://dx.doi.org/10.1182/blood-2016-09-696013] [PMID: 28159740]
[81]
Corbin, A.S.; Agarwal, A.; Loriaux, M.; Cortes, J.; Deininger, M.W.; Druker, B.J. Human chronic myeloid leukemia stem cells are insensitive to imatinib despite inhibition of BCR-ABL activity. J. Clin. Invest., 2011, 121(1), 396-409.
[http://dx.doi.org/10.1172/JCI35721] [PMID: 21157039]
[82]
Graham, S.M.; Jørgensen, H.G.; Allan, E.; Pearson, C.; Alcorn, M.J.; Richmond, L.; Holyoake, T.L. Primitive, quiescent, Philadelphia-positive stem cells from patients with chronic myeloid leukemia are insensitive to STI571 in vitro. Blood, 2002, 99(1), 319-325.
[http://dx.doi.org/10.1182/blood.V99.1.319] [PMID: 11756187]
[83]
Jørgensen, H.G.; Allan, E.K.; Jordanides, N.E.; Mountford, J.C.; Holyoake, T.L. Nilotinib exerts equipotent antiproliferative effects to imatinib and does not induce apoptosis in CD34+ CML cells. Blood, 2007, 109(9), 4016-4019.
[http://dx.doi.org/10.1182/blood-2006-11-057521] [PMID: 17213283]
[84]
Nelson, E.A.; Walker, S.R.; Weisberg, E.; Bar-Natan, M.; Barrett, R.; Gashin, L.B.; Terrell, S.; Klitgaard, J.L.; Santo, L.; Addorio, M.R.; Ebert, B.L.; Griffin, J.D.; Frank, D.A. The STAT5 inhibitor pimozide decreases survival of chronic myelogenous leukemia cells resistant to kinase inhibitors. Blood, 2011, 117(12), 3421-3429.
[http://dx.doi.org/10.1182/blood-2009-11-255232] [PMID: 21233313]
[85]
Prost, S.; Relouzat, F.; Spentchian, M.; Ouzegdouh, Y.; Saliba, J.; Massonnet, G.; Beressi, J-P.; Verhoeyen, E.; Raggueneau, V.; Maneglier, B.; Castaigne, S.; Chomienne, C.; Chrétien, S.; Rousselot, P.; Leboulch, P. Erosion of the chronic myeloid leukaemia stem cell pool by PPARγ agonists. Nature, 2015, 525(7569), 380-383.
[http://dx.doi.org/10.1038/nature15248] [PMID: 26331539]
[86]
Müller, J.; Sperl, B.; Reindl, W.; Kiessling, A.; Berg, T. Discovery of chromone-based inhibitors of the transcription factor STAT5. ChemBioChem, 2008, 9(5), 723-727.
[http://dx.doi.org/10.1002/cbic.200700701] [PMID: 18247434]
[87]
Rondanin, R.; Simoni, D.; Romagnoli, R.; Baruchello, R.; Marchetti, P.; Costantini, C.; Fochi, S.; Padroni, G.; Grimaudo, S.; Pipitone, R.M.; Meli, M.; Tolomeo, M. Inhibition of activated STAT5 in Bcr/Abl expressing leukemia cells with new pimozide derivatives. Bioorg. Med. Chem. Lett., 2014, 24(18), 4568-4574.
[http://dx.doi.org/10.1016/j.bmcl.2014.07.069] [PMID: 25131537]
[88]
Rondanin, R.; Simoni, D.; Maccesi, M.; Romagnoli, R.; Grimaudo, S.; Pipitone, R.M.; Meli, M.; Cascio, A.; Tolomeo, M. Effects of pimozide derivatives on pSTAT5 in K562 cells. ChemMedChem, 2017, 12(15), 1183-1190.
[http://dx.doi.org/10.1002/cmdc.201700234] [PMID: 28657677]
[89]
Grimaudo, S.; Meli, M.; Di Cristina, A.; Ferro, A.; Pipitone, M.R.; Romagnoli, R.; Simoni, D.; Dieli, F.; Tolomeo, M. The new iodoacetamidobenzofuran derivative TR120 decreases STAT5 expression and induces antitumor effects in imatinib-sensitive and imatinib-resistant BCR-ABL-expressing leukemia cells. Anticancer Drugs, 2013, 24(4), 384-393.
[http://dx.doi.org/10.1097/CAD.0b013e32835e64a0] [PMID: 23370613]
[90]
Romagnoli, R.; Baraldi, P.G.; Prencipe, F.; Lopez-Cara, C.; Rondanin, R.; Simoni, D.; Hamel, E.; Grimaudo, S.; Pipitone, R.M.; Meli, M.; Tolomeo, M. Novel iodoacetamido benzoheterocyclic derivatives with potent antileukemic activity are inhibitors of STAT5 phosphorylation. Eur. J. Med. Chem., 2016, 108(108), 39-52.
[http://dx.doi.org/10.1016/j.ejmech.2015.11.022] [PMID: 26629859]
[91]
Page, B.D.G.; Khoury, H.; Laister, R.C.; Fletcher, S.; Vellozo, M.; Manzoli, A.; Yue, P.; Turkson, J.; Minden, M.D.; Gunning, P.T. Small molecule STAT5-SH2 domain inhibitors exhibit potent antileukemia activity. J. Med. Chem., 2012, 55(3), 1047-1055.
[http://dx.doi.org/10.1021/jm200720n] [PMID: 22148584]
[92]
Cumaraswamy, A.A.; Lewis, A.M.; Geletu, M.; Todic, A.; Diaz, D.B.; Cheng, X.R.; Brown, C.E.; Laister, R.C.; Muench, D.; Kerman, K.; Grimes, H.L.; Minden, M.D.; Gunning, P.T. Nanomolar-Potency small molecule inhibitor of STAT5 protein. ACS Med. Chem. Lett., 2014, 5(11), 1202-1206.
[http://dx.doi.org/10.1021/ml500165r] [PMID: 25419444]
[93]
Liao, Z.; Gu, L.; Vergalli, J.; Mariani, S.A.; De Dominici, M.; Lokareddy, R.K.; Dagvadorj, A.; Purushottamachar, P.; McCue, P.A.; Trabulsi, E.; Lallas, C.D.; Gupta, S.; Ellsworth, E.; Blackmon, S.; Ertel, A.; Fortina, P.; Leiby, B.; Xia, G.; Rui, H.; Hoang, D.T.; Gomella, L.G.; Cingolani, G.; Njar, V.; Pattabiraman, N.; Calabretta, B.; Nevalainen, M.T. Structure-based screen identifies a potent small molecule inhibitor of Stat5a/b with therapeutic potential for prostate cancer and chronic myeloid leukemia. Mol. Cancer Ther., 2015, 14(8), 1777-1793.
[http://dx.doi.org/10.1158/1535-7163.MCT-14-0883] [PMID: 26026053]
[94]
Wang, X.; Zeng, J.; Shi, M.; Zhao, S.; Bai, W.; Cao, W.; Tu, Z.; Huang, Z.; Feng, W. Targeted blockage of signal transducer and activator of transcription 5 signaling pathway with decoy oligodeoxynucleotides suppresses leukemic K562 cell growth. DNA Cell Biol., 2011, 30(2), 71-78.
[http://dx.doi.org/10.1089/dna.2010.1112] [PMID: 21091189]
[95]
Kaymaz, B.T.; Selvi, N.; Gündüz, C.; Aktan, C.; Dalmızrak, A.; Saydam, G.; Kosova, B. Repression of STAT3, STAT5A, and STAT5B expressions in chronic myelogenous leukemia cell line K-562 with unmodified or chemically modified siRNAs and induction of apoptosis. Ann. Hematol., 2013, 92(2), 151-162.
[http://dx.doi.org/10.1007/s00277-012-1575-2] [PMID: 23053176]
[96]
Wu, L.; Li, Y.; Fan, J-M.; Zhang, Z-M.; Ouyang, J-L.; Ni, T-T.; Wu, H-X.; Li, H. MicroRNA-204 targets signal transducer and activator of transcription 5 expression and inhibits proliferation of B-cell lymphoma cells. Mol. Med. Rep., 2015, 11(6), 4567-4572.
[http://dx.doi.org/10.3892/mmr.2015.3298] [PMID: 25651400]
[97]
Liu, S.; Walker, S.R.; Nelson, E.A.; Cerulli, R.; Xiang, M.; Toniolo, P.A.; Qi, J.; Stone, R.M.; Wadleigh, M.; Bradner, J.E.; Frank, D.A. Targeting STAT5 in hematologic malignancies through inhibition of the Bromodomain and Extra-Terminal (BET) bromodomain protein BRD2. Mol. Cancer Ther., 2014, 13(5), 1194-1205.
[http://dx.doi.org/10.1158/1535-7163.MCT-13-0341] [PMID: 24435449]
[98]
Liu, L-J.; Wang, W.; Kang, T-S.; Liang, J-X.; Liu, C.; Kwong, D.W.J.; Wong, V.K.W.; Ma, D-L.; Leung, C-H. Antagonizing STAT5B dimerization with an osmium complex. Sci. Rep., 2016, 6(1), 36044.
[http://dx.doi.org/10.1038/srep36044] [PMID: 27853239]
[99]
Elumalai, N.; Berg, A.; Rubner, S.; Blechschmidt, L.; Song, C.; Natarajan, K.; Matysik, J.; Berg, T. Rational development of Stafib-2: A selective, nanomolar inhibitor of the transcription factor STAT5b. Sci. Rep., 2017, 7(1), 819.
[http://dx.doi.org/10.1038/s41598-017-00920-3] [PMID: 28400581]
[100]
Wingelhofer, B.; Maurer, B.; Heyes, E.C.; Cumaraswamy, A.A.; Berger-Becvar, A.; de Araujo, E.D.; Orlova, A.; Freund, P.; Ruge, F.; Park, J.; Tin, G.; Ahmar, S.; Lardeau, C.H.; Sadovnik, I.; Bajusz, D.; Keserű, G.M.; Grebien, F.; Kubicek, S.; Valent, P.; Gunning, P.T.; Moriggl, R. Pharmacologic inhibition of STAT5 in acute myeloid leukemia. Leukemia, 2018, 32(5), 1135-1146.
[http://dx.doi.org/10.1038/s41375-017-0005-9] [PMID: 29472718]
[101]
Loh, C-Y.; Arya, A.; Naema, A.F.; Wong, W.F.; Sethi, G.; Looi, C.Y. Signal Transducer and Activator of Transcription (STATs) proteins in cancer and inflammation: Functions and therapeutic implication. Front. Oncol., 2019, 9, 48.
[http://dx.doi.org/10.3389/fonc.2019.00048] [PMID: 30847297]
[102]
Rousselot, P.; Prost, S.; Guilhot, J.; Roy, L.; Etienne, G.; Legros, L.; Charbonnier, A.; Coiteux, V.; Cony-Makhoul, P.; Huguet, F.; Cayssials, E.; Cayuela, J.M.; Relouzat, F.; Delord, M.; Bruzzoni-Giovanelli, H.; Morisset, L.; Mahon, F.X.; Guilhot, F.; Leboulch, P.; French, C.M.L. French CML Group. Pioglitazone together with imatinib in chronic myeloid leukemia: A proof of concept study. Cancer, 2017, 123(10), 1791-1799.
[http://dx.doi.org/10.1002/cncr.30490] [PMID: 28026860]
[103]
Bartalucci, N.; Calabresi, L.; Balliu, M.; Martinelli, S.; Rossi, M.C.; Villeval, J.L.; Annunziato, F.; Guglielmelli, P.; Vannucchi, A.M. Inhibitors of the PI3K/mTOR pathway prevent STAT5 phosphorylation in JAK2V617F mutated cells through PP2A/CIP2A axis. Oncotarget, 2017, 8(57), 96710-96724.
[http://dx.doi.org/10.18632/oncotarget.18073] [PMID: 29228564]
[104]
Duong, J.K.; Griffin, M.J.; Hargrave, D.; Vormoor, J.; Edwards, D.; Boddy, A.V. A population pharmacokinetic model of AT9283 in adults and children to predict the maximum tolerated dose in children with leukaemia. Br. J. Clin. Pharmacol., 2017, 83(8), 1713-1722.
[http://dx.doi.org/10.1111/bcp.13260] [PMID: 28177130]

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