Důležitá role STAT3 v biologii chronické lymfocytární leukemie

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Autoři: M. Boudny; M. Trbusek
Působiště autorů: Department of Internal Medicine, Hematology and Oncology, Faculty of Medicine, Masaryk University and University Hospital Brno
Vyšlo v časopise: Klin Onkol 2020; 33(1): 32-38
Kategorie: Přehled
doi: https://doi.org/10.14735/amko202032

Souhrn

Východiska: Proteiny STAT (signal transducer and activator of transcription) jsou cytoplazmatické transkripční faktory, které přenášejí signál cytokinů, hormonů a růstových faktorů. Proteiny STAT kontrolují základní buněčné procesy vč. přežití, proliferace a diferenciace. Nadměrná aktivace proteinů STAT může přispět k transformaci buněk a vzniku leukemie. Okolo 70 % všech solidních a hematologických nádorů vykazuje aberantní expresi a/nebo aktivaci STAT3, což dokumentuje zásadní roli STAT3 v tumorigenezi. Aberantní aktivace STAT3 byla popsána u několika solidních nádorů a hematologických malignit. Důležité je, že konstitutivní aktivace proteinů STAT byla detekována u několika typů leukemie vč. akutní myeloidní leukemie, akutní promyelocytární leukemie, akutní lymfoblastické leukemie, chronické myeloidní leukemie a chronické lymfocytární leukemie (CLL). Konstitutivně aktivovaný STAT3 hraje důležitou roli v biologii CLL. Buňky CLL jsou konstitutivně fosforylované na S727 a acetylované na K685, navíc může dojít i k fosforylaci na Y705. Exprese mediátorové RNA STAT3 je výrazně vyšší v buňkách CLL ve srovnání se zdravými B lymfocyty. Zajímavé je, že inhibice STAT3 byla popsána jako důležitý vedlejší produkt léčby ibrutinibem u pacientů s CLL.

Cíl: Účelem tohoto přehledu je popsat důsledky deregulace STAT3 u buněk CLL. V práci jsou popsány procesy ovlivněné nadměrnou aktivací STAT3 jako proliferace, apoptóza, signalizace BCR (B cell receptor), sekrece cytokinů, regulace kontrolních bodů imunitního systému, regulace mikroRNA, metabolizmus mastných kyselin a elektronový transportní řetězec v mitochondriích.

Práce byla podpořena projektem FNBr 65269705 – koncepční rozvoj výzkumné organizace a projektem MUNI/A/1105/2018.

Autoři deklarují, že v souvislosti s předmětem studie nemají žádné komerční zájmy.

Redakční rada potvrzuje, že rukopis práce splnil ICMJE kritéria pro publikace zasílané do biomedicínských č asopisů.

Obdrženo: 11. 9. 2019

Přijato: 6. 11. 2019

Klíčová slova:

STAT3 – STAT – chronická lymfocytární leukemie – terapie – mikroprostředí – ibrutinib – konstitutivní aktivace – leukemie

Zdroje

1. Yu H, Pardoll D, Jove R. STATs in cancer inflammation and immunity: a leading role for STAT3. Nat Rev Cancer 2009; 9 (11): 798–809. doi: 10.1038/nrc2734.

2. Hayakawa F, Towatari M, Iida H et al. Differential constitutive activation between STAT-related proteins and MAP kinase in primary acute myelogenous leukaemia. Br J Haematol 1998; 101 (3): 521–528. 10.1046/j.1365-2141.1998.00720.x.

3. 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: 3173–3180.

4. 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): 5701–5709. doi: 10.1182/blood-2010-04-280123.

5. Dong S, Chen SJ, Tweardy DJ. Cross-talk between retinoic acid and STAT3 signaling pathways in acute promyelocytic leukemia. Leuk Lymphoma 2003; 44 (12): 2023–2029. doi: 10.1080/1042819031000116670.

6. Gouilleux-Gruart V, Gouilleux F, Desaint C et al. STAT-related transcription factors are constitutively activated in peripheral blood cells from acute leukemia patients. Blood 1996; 87 (5): 1692–1697.

7. Frank DA, 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.

8. Hazan-Halevy I, Harris D, Liu Z et al. STAT3 is constitutively phosphorylated on serine 727 residues, binds DNA, and activates transcription in CLL cells. Blood 2010; 115 (14): 2852–2863. doi: 10.1182/blood-2009-10-230060.

9. Frank DA, Mahajan S, Ritz J. B lymphocytes from patients with chronic lymphocytic leukemia contain signal transducer and activator of transcription (STAT) 1 and STAT3 constitutively phosphorylated on serine residues. J Clin Invest 1997; 100 (12): 3140–3148. doi: 10.1172/JCI119869.

10. Rozovski U, Harris DM, Li P et al. STAT3 is constitutively acetylated on lysine 685 residues in chronic lymphocytic leukemia cells. Oncotarget 2018; 9 (72): 33710–33718. doi: 10.18632/oncotarget.26110.

11. Grivennikov SI, Karin M. Dangerous liaisons: STAT3 and NF-B collaboration and crosstalk in cancer. Cytokine Growth Factor Rev 2010; 21 (1): 11–19. doi: 10.1016/j.cytogfr.2009.11.005.

12. Yu H, Jove R. The STATs of cancer – new molecular targets come of age. Nat Rev Cancer 2004; 4 (2): 97–105. doi: 10.1038/nrc1275.

13. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell 2011; 144 (5): 646–674. doi: 10.1016/ j.cell.2011.02.013.

14. Takeda K, Noguchi K, Shi W et al. Targeted disruption of the mouse Stat3 gene leads to early embryonic lethality. Proc Natl Acad Sci 1997; 94 (8): 3801–3804. doi: 10.1073/pnas.94.8.3801.

15. 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): 3797–3802. doi: 10.1182/blood-2013-10-534073.

16. Kondo K, Shaim H, Thompson PA et al. Ibrutinib modulates the immunosuppressive CLL microenvironment through STAT3-mediated suppression of regulatory B-cell function and inhibition of the PD-1/PD-L1 pathway. Leukemia 2018; 32 (4): 960–970. doi: 10.1038/leu.2017. 304.

17. Antosz H, Wojciechowska K, Sajewicz J et al. IL-6, IL-10, c-Jun and STAT3 expression in B-CLL. Blood Cells Mol Dis 2015; 54 (3): 258–265. doi: 10.1016/j.bcmd.2014.11. 006.

18. Chen N, Feng L, Qu H et al. Overexpression of IL-9 induced by STAT3 phosphorylation is mediated by miR-155 and miR-21 in chronic lymphocytic leukemia. Oncol Rep 2018; 39 (6): 3064–3072. doi: 10.3892/or.2018.6367.

19. Lin F, Wu D, Fang D et al. STAT3-induced SMYD3 transcription enhances chronic lymphocytic leukemia cell growth in vitro and in vivo. Inflamm Res 2019; 68 (9): 739–749. doi: 10.1007/s00011-019-01257-5.

20. Myhrvold IK, Cremaschi A, Hermansen JU et al. Single cell profiling of phospho-protein levels in chronic lymphocytic leukemia. Oncotarget 2018; 9 (10): 9273–9284. doi: 10.18632/oncotarget.23949.

21. Rozovski U, Harris DM, Li P et al. Constitutive phosphorylation of STAT3 by the CK2–BLNK–CD5 complex. Mol Cancer Res 2017; 15 (5): 610–618. doi: 10.1158/1541-7786.MCR-16-0291.

22. Liu FT, Jia L, Wang P et al. STAT3 and NF-B cooperatively control in vitro spontaneous apoptosis and poor chemo-responsiveness in patients with chronic lymphocytic leukemia. Oncotarget 2016; 7 (22): 32031–32045. doi: 10.18632/oncotarget.8672.

23. Yang J, Liao X, Agarwal MK et al. Unphosphorylated STAT3 accumulates in response to IL-6 and activates transcription by binding to NFkappaB. Genes Dev 2007; 21 (11): 1396–1408. doi: 10.1101/gad.1553707.

24. Liu Z, Hazan-Halevy I, Harris DM et al. STAT-3 activates NF-kappaB in chronic lymphocytic leukemia cells. Mol Cancer Res 2011; 9 (4): 507–515. doi: 10.1158/1541-7786.MCR-10-0559.

25. Li P, Harris D, Liu Z et al. STAT3-activated GM-CSFR translocates to the nucleus and protects CLL cells from apoptosis. Mol Cancer Res 2014; 12 (9): 1267–1282. doi: 10.1158/1541-7786.MCR-13-0652-T.

26. Rozovski U, Harris DM, Li P et al. At high levels, constitutively activated STAT3 induces apoptosis of chronic lymphocytic leukemia cells. J Immunol 2016; 196 (10): 4400–4409. doi: 10.4049/jimmunol.1402108.

27. Chen Y, Chen L, Yu J et al. Cirmtuzumab blocks Wnt5a/ROR1-stimulation of NF-B to repress autocrine STAT3-activation in chronic lymphocytic leukemia. Blood 2019; 134 (13): 1084–1094. doi: 10.1182/blood.2019001366.

28. Herishanu Y, Pérez-Galán P, Liu D et al. The lymph node microenvironment promotes B-cell receptor signaling, NF-kappaB activation, and tumor proliferation in chronic lymphocytic leukemia. Blood 2011; 117 (2): 563–574. doi: 10.1182/blood-2010-05-284984.

29. Rozovski U, Harris DM, Li P et al. Activation of the B-cell receptor successively activates NF-B and STAT3 in chronic lymphocytic leukemia cells. Int J Cancer 2017; 141 (10): 2076–2081. doi: 10.1002/ijc.30892.

30. Shaim H, Estrov Z, Harris D et al. The CXCR4–STAT3–IL-10 pathway controls the immunoregulatory function of chronic lymphocytic leukemia and is modulated by lenalidomide. Front Immunol 2018; 8: 1773. doi: 10.3389/fimmu.2017.01773.

31. Rozovski U, Calin GA, Setoyama T et al. Signal transducer and activator of transcription (STAT) -3 regulates microRNA gene expression in chronic lymphocytic leukemia cells. Mol Cancer 2013; 12: 50. doi: 10.1186/1476-4598-12-50.

32. Li P, Grgurevic S, Liu Z et al. Signal transducer and activator of transcription–3 induces microRNA-155 expression in chronic lymphocytic leukemia. PLoS ONE 2013; 8 (6): e64678. doi: 10.1371/journal.pone.0064678.

33. Xu-Monette ZY, Zhou J, Young KH. PD-1 expression and clinical PD-1 blockade in B-cell lymphomas. Blood 2018; 131 (1): 68–83. doi: 10.1182/blood-2017-07-740993.

34. Darvin P, Toor SM, Sasidharan Nair V et al. Immune checkpoint inhibitors: recent progress and potential biomarkers. Exp Mol Med 2018; 50 (12): 165. doi: 10.1038/s12276-018-0191-1.

35. Ma C, Horlad H, Pan C et al. Stat3 inhibitor abrogates the expression of PD-1 ligands on lymphoma cell lines. J Clin Exp Hematop 2017; 57 (1): 21–25. doi: 10.3960/jslrt.17006.

36. Wegrzyn J, Potla R, Chwae YJ et al. Function of mitochondrial Stat3 in cellular respiration. Science 2009; 323 (5915): 793–797. doi: 10.1126/science.1164551.

37. Capron C, Jondeau K, Casetti L et al. Viability and stress protection of chronic lymphoid leukemia cells involves overactivation of mitochondrial phosphoSTAT3Ser727. Cell Death Dis 2014; 5: e1451. doi: 10.1038/cddis.2014. 393.

38. Rozovski U, Grgurevic S, Bueso-Ramos C et al. Aberrant LPL expression, driven by STAT3, mediates free fatty acid metabolism in CLL cells. Mol Cancer Res 2015; 13 (5): 944–953. doi: 10.1158/1541-7786.MCR-14-0412.

39. Rozovski U, Harris DM, Li P et al. STAT3-activated CD36 facilitates fatty acid uptake in chronic lymphocytic leukemia cells. Oncotarget 2018; 9 (30): 21268–21280. doi: 10.18632/oncotarget.25066.

40. Ishdorj G, Johnston JB, Gibson SB. Inhibition of constitutive activation of STAT3 by curcurbitacin-I (JSI-124) sensitized human B-leukemia cells to apoptosis. Mol Cancer Ther 2010; 9 (12): 3302–3314. doi: 10.1158/1535-7163.MCT-10-0550.

41. Chen TL, Gupta N, Lehman A et al. Hsp90 inhibition increases SOCS3 transcript and regulates migration and cell death in chronic lymphocytic leukemia. Oncotarget 2016; 7 (19): 28684–28696. doi: 10.18632/oncotarget.8760.

42. Brown JR, Walker SR, Heppler LN et al. A clinical trial of the STAT3 inhibitor pyrimethamine in chronic lymphocytic leukemia. Blood 2018; 132: 1855–1855.

43. clinicaltrials.gov. Pyrimethamine for the treatment of relapsed chronic lymphocytic leukemia/small lymphocytic lymphoma. [online]. Available from: https: //clinicaltrials.gov/ct2/show/NCT01066663.

44. Takakura A, Nelson EA, Haque N et al. Pyrimethamine inhibits adult polycystic kidney disease by modulating STAT signaling pathways. Hum Mol Genet 2011; 20 (21): 4143–4154. doi: 10.1093/hmg/ddr 338.

45. Legorreta-Herrera M, Retana-Ugalde R, Ventura-Gallegos JL et al. Pyrimethamine induces oxidative stress in Plasmodium yoelii 17XL-infected mice: a novel immunomodulatory mechanism of action for an old antimalarial drug? Exp Parasitol 2010; 126 (3): 381–388. doi: 10.1016/j.exppara.2010.02.013.

46. Khan MW, Saadalla A, Ewida AH et al. The STAT3 inhibitor pyrimethamine displays anti-cancer and immune stimulatory effects in murine models of breast cancer. Cancer Immunol Immunother 2018; 67 (1): 13–23. doi: 10.1007/s00262-017-2057-0.

47. Inghirami G, Chiarle R, Simmons WJ et al. New and old functions of STAT3: a pivitol target for individualized treatment of cancer. Cell Cycle 2005; 4 (9): 1131–1133. doi: 10.4161/cc.4.9.1985.

48. Doshi UA, Shaw J, Fox TE et al. STAT3 mediates C6-ceramide-induced cell death in chronic lymphocytic leukemia. Signal Transduct Target Ther 2017; 2: 17051. doi: 10.1038/sigtrans.2017.51.