Antagonistic activities of the immunomodulator and PP2A-activating drug FTY720 (Fingolimod, Gilenya) in Jak2-driven hematologic malignancies

Blood

Volumn 122, Issue 11, 2013, Pages 1923-1934

  Oaks, Joshua J ^a   Santhanam, Ramasamy ^a,b   Walker, Christopher J ^a   Roof, Steve ^a   Harb, Jason G ^a   Ferenchak, Greg ^a   Eisfeld, Ann Kathrin ^a   Van Brocklyn, James R ^a   Briesewitz, Roger ^a,c   Saddoughi, Sahar A ^d   Nagata, Kyosuke ^e   Bittman, Robert ^f   Caligiuri, Michael A ^b,c   Abdel Wahab, Omar ^g   Levine, Ross ^g   Arlinghaus, Ralph B ^h   Quintas Cardama, Alfonso ⁱ   Goldman, John M ^j   Apperley, Jane ^j   Reid, Alistair ^j   Milojkovic, Dragana ^j   Ziolo, Mark T ^a   Marcucci, Guido ^b,c   Ogretmen, Besim ^d   Neviani, Paolo ^a   Perrotti, Danilo ^a,c,j   more..

^a OHIO STATE UNIVERSITY   (United States)

^b THE OHIO STATE UNIVERSITY WEXNER MEDICAL CENTER   (United States)

^c OHIO STATE UNIVERSITY   (United States)

^d MEDICAL UNIVERSITY OF SOUTH CAROLINA   (United States)

^e UNIVERSITY OF TSUKUBA   (Japan)

^f CITY UNIVERSITY OF NEW YORK   (United States)

^g MEMORIAL SLOAN KETTERING CANCER CENTER   (United States)

^h MD Anderson Cancer Center ^*  (United States)

ⁱ UNIVERSITY OF TEXAS MD ANDERSON CANCER CENTER   (United States)

^j HAMMERSMITH HOSPITAL   (United Kingdom)

more..

Author keywords

[No Author keywords available]

Indexed keywords

2 AMINO 2 (3 OCTYLPHENYLCARBAMOYL)ETHYL PHOSPHATE; 5 (4 PHENYL 5 TRIFLUOROMETHYL 2 THIENYL) 3 (3 TRIFLUOROMETHYLPHENYL) 1,2,4 OXADIAZOLE; 5 [(2,2 DIFLUORO 1,3 BENZODIOXOL 5 YL)METHYLIDENE] 2,4 THIAZOLIDINEDIONE; CERAMIDE; FEDRATINIB; FINGOLIMOD; GROWTH FACTOR RECEPTOR BOUND PROTEIN 2; ISOPRENALINE; JANUS KINASE 2; MESSENGER RNA; MIDOSTAURIN; N BENZYL 2 CYANO 3 (3,4 DIHYDROXYPHENYL)ACRYLAMIDE; PHOSPHOPROTEIN PHOSPHATASE 2A; SHORT HAIRPIN RNA; SPHINGOSINE 1 PHOSPHATE; SPHINGOSINE 1 PHOSPHATE RECEPTOR; SPHINGOSINE KINASE 1; DRUG DERIVATIVE; IMMUNOSUPPRESSIVE AGENT; ONCOPROTEIN; PHOSPHATIDYLINOSITOL 4,5 BISPHOSPHATE 3 KINASE; PHOSPHOPROTEIN PHOSPHATASE 2; PIK3CG PROTEIN, MOUSE; PROPANEDIOL DERIVATIVE; PROTEIN KINASE C; SET PROTEIN, MOUSE; SPHINGOSINE;

ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; ANTINEOPLASTIC ACTIVITY; ARTICLE; BLAST CELL CRISIS; CANCER INHIBITION; CELLULAR DISTRIBUTION; CHRONIC MYELOID LEUKEMIA; CLONOGENESIS; CONTROLLED STUDY; DIMERIZATION; DRUG SAFETY; ENZYME INACTIVATION; ENZYME INHIBITION; ERYTHROLEUKEMIA CELL; HEMATOLOGIC MALIGNANCY; HUMAN; HUMAN CELL; IN VIVO STUDY; LD50; LEUKEMIA CELL; LEUKEMOGENESIS; LONG TERM CARE; LUNG ALVEOLUS CELL; MEDIAN SURVIVAL TIME; MOUSE; MYELOPROLIFERATIVE NEOPLASM; NONHUMAN; POLYCYTHEMIA VERA; PRIORITY JOURNAL; PROTEIN PHOSPHORYLATION; SPLENOMEGALY; ANIMAL; CELL CULTURE; CELL LINE; DRUG EFFECT; ENZYME ACTIVATION; GENETICS; IMMUNOBLOTTING; KAPLAN MEIER METHOD; LEUKEMIA; METABOLISM; MUTATION; PATHOLOGY; REVERSE TRANSCRIPTION POLYMERASE CHAIN REACTION; RNA INTERFERENCE; SCID MOUSE; SIGNAL TRANSDUCTION; TREATMENT OUTCOME; TUMOR CELL LINE;

ANIMALS; CELL LINE, TRANSFORMED; CELL LINE, TUMOR; CELLS, CULTURED; CLASS IB PHOSPHATIDYLINOSITOL 3-KINASE; ENZYME ACTIVATION; HUMANS; IMMUNOBLOTTING; IMMUNOSUPPRESSIVE AGENTS; JANUS KINASE 2; KAPLAN-MEIER ESTIMATE; LEUKEMIA; MICE; MICE, SCID; MUTATION; ONCOGENE PROTEINS; PROPYLENE GLYCOLS; PROTEIN KINASE C; PROTEIN PHOSPHATASE 2; REVERSE TRANSCRIPTASE POLYMERASE CHAIN REACTION; RNA INTERFERENCE; SIGNAL TRANSDUCTION; SPHINGOSINE; TREATMENT OUTCOME;

EID: 84887391984     PISSN: 00064971     EISSN: 15280020     Source Type: Journal    
DOI: 10.1182/blood-2013-03-492181     Document Type: Article

References (50)

1. Ingwersen J, Aktas O, Kuery P, Kieseier B, Boyko A, Hartung HP. Fingolimod in multiple sclerosis: mechanisms of action and clinical efficacy. Clin Immunol. 2012;142(1):15-24.
2. Perrotti D, Neviani P. Protein phosphatase 2A: a target for anticancer therapy. Lancet Oncol. 2013;14(6):e229-e238.
3. Neviani P, Santhanam R, Oaks JJ, et al. FTY720, a new alternative for treating blast crisis chronic myelogenous leukemia and Philadelphia chromosome-positive acute lymphocytic leukemia. J Clin Invest. 2007;117(9):2408-2421.
4. Neviani P, Santhanam R, Trotta R, et al. The tumor suppressor PP2A is functionally inactivated in blast crisis CML through the inhibitory activity of the BCR/ABL-regulated SET protein. Cancer Cell. 2005;8(5):355-368.
5. Baxter EJ, Scott LM, Campbell PJ, et al; Cancer Genome Project. Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders. Lancet. 2005;365(9464):1054-1061.
6. James C, Ugo V, Le Couédic JP, et al. A unique clonal JAK2 mutation leading to constitutive signalling causes polycythaemia vera. Nature. 2005;434(7037):1144-1148.
7. Jamieson CH, Gotlib J, Durocher JA, et al. The JAK2 V617F mutation occurs in hematopoietic stem cells in polycythemia vera and predisposes toward erythroid differentiation. Proc Natl Acad Sci USA. 2006;103(16):6224-6229.
8. Levine RL, Wadleigh M, Cools J, et al. Activating mutation in the tyrosine kinase JAK2 in polycythemia vera, essential thrombocythemia, and myeloid metaplasia with myelofibrosis. Cancer Cell. 2005;7(4):387-397.
9. Kralovics R, Passamonti F, Buser AS, et al. A gain-of-function mutation of JAK2 in myeloproliferative disorders. N Engl J Med. 2005;352(17):1779-1790.
10. Zhao R, Xing S, Li Z, et al. Identification of an acquired JAK2 mutation in polycythemia vera. J Biol Chem. 2005;280(24):22788-22792.
11. Zou H, Yan D, Mohi G. Differential biological activity of disease-associated JAK2 mutants. FEBS Lett. 2011;585(7):1007-1013.
12. Vainchenker W, Constantinescu SN. A unique activating mutation in JAK2 (V617F) is at the origin of polycythemia vera and allows a new classification of myeloproliferative diseases. Hematology Am Soc Hematol Educ Program. 2005;195-200.
13. Li J, Spensberger D, Ahn JS, et al. JAK2 V617F impairs hematopoietic stem cell function in a conditional knock-in mouse model of JAK2 V617F-positive essential thrombocythemia. Blood. 2010;116(9):1528-1538.
14. Tiedt R, Hao-Shen H, Sobas MA, et al. Ratio of mutant JAK2-V617F to wild-type Jak2 determines the MPD phenotypes in transgenic mice. Blood. 2008;111(8):3931-3940.
15. Wernig G, Mercher T, Okabe R, Levine RL, Lee BH, Gilliland DG. 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.
16. Shide K, Shimoda HK, Kumano T, et al. Development of ET, primary myelofibrosis and PV in mice expressing JAK2 V617F. Leukemia. 2008; 22(1):87-95.
17. Xing S, Wanting TH, Zhao W, et al. Transgenic expression of JAK2V617F causes myeloproliferative disorders in mice. Blood. 2008; 111(10):5109-5117.
18. LaFave LM, Levine RL. JAK2 the future: therapeutic strategies for JAK-dependent malignancies. Trends Pharmacol Sci. 2012; 33(11):574-582.
19. Tefferi A, Pardanani A. JAK inhibitors in myeloproliferative neoplasms: rationale, current data and perspective. Blood Rev. 2011;25(5): 229-237.
20. Quintás-Cardama A, Kantarjian H, Cortes J, Verstovsek S. Janus kinase inhibitors for the treatment of myeloproliferative neoplasias and beyond. Nat Rev Drug Discov. 2011;10(2): 127-140.
21. Verstovsek S, Kantarjian H, Mesa RA, et al. Safety and efficacy of INCB018424, a JAK1 and JAK2 inhibitor, in myelofibrosis. N Engl J Med. 2010;363(12):1117-1127.
22. Quintás-Cardama A, Vaddi K, Liu P, et al. Preclinical characterization of the selective JAK1/2 inhibitor INCB018424: therapeutic implications for the treatment of myeloproliferative neoplasms. Blood. 2010;115(15):3109-3117.
23. Adachi Y, Pavlakis GN, Copeland TD. Identification of in vivo phosphorylation sites of SET, a nuclear phosphoprotein encoded by the translocation breakpoint in acute undifferentiated leukemia. FEBS Lett. 1994;340(3):231-235.
24. Samanta AK, Chakraborty SN, Wang Y, et al. Jak2 inhibition deactivates Lyn kinase through the SET-PP2A-SHP1 pathway, causing apoptosis in drug-resistant cells from chronic myelogenous leukemia patients. Oncogene. 2009;28(14): 1669-1681.
25. Vasudevan NT, Mohan ML, Gupta MK, Hussain AK, Naga Prasad SV. Inhibition of protein phosphatase 2A activity by PI3Kg regulates b-adrenergic receptor function. Mol Cell. 2011; 41(6):636-648.
26. ten Klooster JP, Leeuwen I, Scheres N, Anthony EC, Hordijk PL. Rac1-induced cell migration requires membrane recruitment of the nuclear oncogene SET. EMBO J. 2007;26(2):336-345.
27. Begum N, Ragolia L. Role of janus kinase-2 in insulin-mediated phosphorylation and inactivation of protein phosphatase-2A and its impact on upstream insulin signalling components. Biochem J. 1999;344(Pt 3):895-901.
28. Ganeshaguru K, Wickremasinghe RG, Jones DT, et al. Actions of the selective protein kinase C inhibitor PKC412 on B-chronic lymphocytic leukemia cells in vitro. Haematologica. 2002; 87(2):167-176.
29. Lee H, Deng J, Kujawski M, et al. STAT3-induced S1PR1 expression is crucial for persistent STAT3 activation in tumors. Nat Med. 2010;16(12): 1421-1428.
30. Abe M, Funakoshi-Tago M, Tago K, et al. The polycythemia vera-associated Jak2 V617F mutant induces tumorigenesis in nude mice. Int Immunopharmacol. 2009;9(7-8):870-877.
31. Schmouder R, Hariry S, David OJ. Placebocontrolled study of the effects of fingolimod on cardiac rate and rhythm and pulmonary function in healthy volunteers. Eur J Clin Pharmacol. 2012; 68(4):355-362.
32. Gräler MH, Goetzl EJ. The immunosuppressant FTY720 down-regulates sphingosine 1-phosphate G-protein-coupled receptors. FASEB J. 2004; 18(3):551-553.
33. Saydam G, Aydin HH, Sahin F, et al. Involvement of protein phosphatase 2A in interferon-alpha-2binduced apoptosis in K562 human chronic myelogenous leukaemia cells. Leuk Res. 2003; 27(8):709-717.
34. Lim KG, Tonelli F, Li Z, et al. FTY720 analogues as sphingosine kinase 1 inhibitors: enzyme inhibition kinetics, allosterism, proteasomal degradation, and actin rearrangement in MCF-7 breast cancer cells. J Biol Chem. 2011;286(21): 18633-18640.
35. Omar HA, Chou CC, Berman-Booty LD, et al. Antitumor effects of OSU-2S, a nonimmunosuppressive analogue of FTY720, in hepatocellular carcinoma. Hepatology. 2011; 53(6):1943-1958.
36. Neviani P, Harb JG, Oaks JJ, et al. PP2Aactivating drugs (PADs) selectively eradicate TKIresistant Ph1 leukemic stem cells. Leukemia. In press.
37. Brinkmann V, Davis MD, Heise CE, et al. The immune modulator FTY720 targets sphingosine 1-phosphate receptors. J Biol Chem. 2002; 277(24):21453-21457.
38. Dobrowsky RT, Kamibayashi C, Mumby MC, Hannun YA. Ceramide activates heterotrimeric protein phosphatase 2A. J Biol Chem. 1993; 268(21):15523-15530.
39. Mukhopadhyay A, Saddoughi SA, Song P, et al. Direct interaction between the inhibitor 2 and ceramide via sphingolipid-protein binding is involved in the regulation of protein phosphatase 2A activity and signaling. FASEB J. 2009;23(3): 751-763.
40. Saddoughi SA, Gencer S, Peterson YK, et al. Sphingosine analogue drug FTY720 targets I2PP2A/SET and mediates lung tumour suppression via activation of PP2A-RIPK1- dependent necroptosis. EMBO Mol Med. 2013; 5(1):105-121.
41. Lu X, Huang LJ, Lodish HF. Dimerization by a cytokine receptor is necessary for constitutive activation of JAK2V617F. J Biol Chem. 2008; 283(9):5258-5266.
42. Yokoyama N, Reich NC, Miller WT. Involvement of protein phosphatase 2A in the interleukin-3- stimulated Jak2-Stat5 signaling pathway. J Interferon Cytokine Res. 2001;21(6):369-378.
43. Newton AC. Lipid activation of protein kinases. J Lipid Res. 2009;50(Suppl):S266-S271.
44. Habrukowich C, Han DK, Le A, et al. Sphingosine interaction with acidic leucine-rich nuclear phosphoprotein-32A (ANP32A) regulates PP2A activity and cyclooxygenase (COX)-2 expression in human endothelial cells. J Biol Chem. 2010; 285(35):26825-26831.
45. Kappos L, Radue EW, O'Connor P, et al; FREEDOMS Study Group. A placebo-controlled trial of oral fingolimod in relapsing multiple sclerosis. N Engl J Med. 2010;362(5):387-401.
46. Ferrand A, Kowalski-Chauvel A, Bertrand C, et al. A novel mechanism for JAK2 activation by a G protein-coupled receptor, the CCK2R: implication of this signaling pathway in pancreatic tumor models. J Biol Chem. 2005;280(11):10710-10715.
47. McDoom I, Ma X, Kirabo A, Lee KY, Ostrov DA, Sayeski PP. Identification of tyrosine 972 as a novel site of Jak2 tyrosine kinase phosphorylation and its role in Jak2 activation. Biochemistry. 2008; 47(32):8326-8334.
48. Barr RK, Lynn HE, Moretti PA, Khew-Goodall Y, Pitson SM. Deactivation of sphingosine kinase 1 by protein phosphatase 2A. J Biol Chem. 2008; 283(50):34994-35002.
49. Goetzl EJ, Kong Y, Mei B. Lysophosphatidic acid and sphingosine 1-phosphate protection of T cells from apoptosis in association with suppression of Bax. J Immunol. 1999;162(4):2049-2056.
50. Saito S, Miyaji-Yamaguchi M, Shimoyama T, Nagata K. Functional domains of templateactivating factor-I as a protein phosphatase 2A inhibitor. Biochem Biophys Res Commun. 1999; 259(2):471-475.