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

被引：96

作者：

Oaks, Joshua J. ^{[1
]}

Santhanam, Ramasamy ^{[1
,2
]}

Walker, Christopher J. ^{[1
]}

Roof, Steve ^{[3
]}

Harb, Jason G. ^{[1
]}

Ferenchak, Greg ^{[1
]}

Eisfeld, Ann-Kathrin ^{[1
]}

Van Brocklyn, James R. ^{[4
]}

Briesewitz, Roger ^{[5
,6
]}

Saddoughi, Sahar A. ^{[7
]}

Nagata, Kyosuke ^{[8
]}

Bittman, Robert ^{[9
]}

Caligiuri, Michael A. ^{[2
,6
]}

Abdel-Wahab, Omar ^{[10
]}

Levine, Ross ^{[10
]}

Arlinghaus, Ralph B. ^{[11
]}

Quintas-Cardama, Alfonso ^{[12
]}

Goldman, John M. ^{[13
]}

Apperley, Jane ^{[13
]}

Reid, Alistair ^{[13
]}

Milojkovic, Dragana ^{[13
]}

Ziolo, Mark T. ^{[3
]}

Marcucci, Guido ^{[2
,6
]}

Ogretmen, Besim ^{[7
]}

Neviani, Paolo ^{[1
]}

Perrotti, Danilo ^{[1
,6
,13
]}

机构：

[1] Ohio State Univ, Human Canc Genet Program, Dept Mol Virol Immunol & Med Genet, Columbus, OH 43210 USA

[2] Ohio State Univ, Dept Internal Med, Columbus, OH 43210 USA

[3] Ohio State Univ, Dept Physiol & Cell Biol, Columbus, OH 43210 USA

[4] Ohio State Univ, Dept Pathol, Columbus, OH 43210 USA

[5] Ohio State Univ, Dept Pharmacol, Columbus, OH 43210 USA

[6] Ohio State Univ, Ctr Comprehens Canc, Columbus, OH 43210 USA

[7] Med Univ S Carolina, Dept Biochem & Mol Biol, Hollings Canc Ctr, Charleston, SC 29425 USA

[8] Univ Tsukuba, Dept Infect Biol, Tsukuba, Ibaraki, Japan

[9] CUNY Queens Coll, Dept Chem & Biochem, Flushing, NY 11367 USA

[10] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA

[11] Univ Texas MD Anderson Canc Ctr, Dept Mol Pathol, Houston, TX 77030 USA

[12] Univ Texas MD Anderson Canc Ctr, Dept Leukemia, Houston, TX 77030 USA

[13] Univ London Imperial Coll Sci Technol & Med, Dept Haematol, Hammersmith Hosp, London, England

来源：

BLOOD | 2013年 / 122卷 / 11期

基金：

美国国家卫生研究院;

关键词：

PROTEIN PHOSPHATASE 2A; CHRONIC MYELOGENOUS LEUKEMIA; TYROSINE KINASE JAK2; POLYCYTHEMIA-VERA; MUTATION; PHOSPHORYLATION; IDENTIFICATION; ACTIVATION; RECEPTOR; CELLS;

D O I：

10.1182/blood-2013-03-492181

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

FTY720 (Fingolimod, Gilenya) is a sphingosine analog used as an immunosuppressant in multiple sclerosis patients. FTY720 is also a potent protein phosphatase 2A (PP2A)-activating drug (PAD). PP2A is a tumor suppressor found inactivated in different types of cancer. We show here that PP2A is inactive in polycythemia vera (PV) and other myeloproliferative neoplasms characterized by the expression of the transforming Jak2(V617F) oncogene. PP2A inactivation occurs in a Jak2(V617F) dose/kinase-dependent manner through the PI-3K gamma-PKC-induced phosphorylation of the PP2A inhibitor SET. Genetic or PAD-mediated PP2A reactivation induces Jak2(V617F) inactivation/downregulation and impairs clonogenic potential of Jak2(V617F) cell lines and PV but not normal CD34(+) progenitors. Likewise, FTY720 decreases leukemic allelic burden, reduces splenomegaly, and significantly increases survival of Jak2(V617F) leukemic mice without adverse effects. Mechanistically, we show that in Jak2(V617F) cells, FTY720 antileukemic activity requires neither FTY720 phosphorylation (FTY720-P) nor SET dimerization or ceramide induction but depends on interaction with SET K209. Moreover, we show that Jak2(V617F) also utilizes an alternative sphingosine kinase-1-mediated pathway to inhibit PP2A and that FTY720-P, acting as a sphingosine-1-phosphate-receptor-1 agonist, elicits signals leading to the Jak2-PI-3K gamma-PKC-SET-mediated PP2A inhibition. Thus, PADs (eg, FTY720) represent suitable therapeutic alternatives for Jak2(V617F) MPNs.

引用

页码：1923 / 1934

页数：12

共 50 条

[1] The polycythemia vera-associated Jak2 V617F mutant induces tumorigenesis in nude mice [J].

Abe, Miyuki ;

Funakoshi-Tago, Megumi ;

Tago, Kenji ;

Kamishimoto, Jun ;

Aizu-Yokota, Eriko ;

Sonoda, Yoshiko ;

Kasahara, Tadashi .

INTERNATIONAL IMMUNOPHARMACOLOGY, 2009, 9 (7-8) :870-877

[2] IDENTIFICATION OF IN-VIVO PHOSPHORYLATION SITES OF SET, A NUCLEAR PHOSPHOPROTEIN ENCODED BY THE TRANSLOCATION BREAKPOINT IN ACUTE UNDIFFERENTIATED LEUKEMIA [J].

ADACHI, Y ;

PAVLAKIS, GN ;

COPELAND, TD .

FEBS LETTERS, 1994, 340 (03) :231-235

[3] Deactivation of Sphingosine Kinase 1 by Protein Phosphatase 2A [J].

Barr, Renae K. ;

Lynn, Helen E. ;

Moretti, Paul A. B. ;

Khew-Goodall, Yeesim ;

Pitson, Stuart M. .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2008, 283 (50) :34994-35002

[4] Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders [J].

Baxter, EJ ;

Scott, LM ;

Campbell, PJ ;

East, C ;

Fourouclas, N ;

Swanton, S ;

Vassiliou, GS ;

Bench, AJ ;

Boyd, EM ;

Curtin, N ;

Scott, MA ;

Erber, WN ;

Green, AR .

LANCET, 2005, 365 (9464) :1054-1061

[5] Role of Janus kinase-2 in insulin-mediated phosphorylation and inactivation of protein phosphatase-2A and its impact on upstream insulin signalling components [J].

Begum, N ;

Ragolia, L .

BIOCHEMICAL JOURNAL, 1999, 344 :895-901

[6] The immune modulator FTY720 targets sphingosine 1-phosphate receptors [J].

Brinkmann, V ;

Davis, MD ;

Heise, CE ;

Albert, R ;

Cottens, S ;

Hof, R ;

Bruns, C ;

Prieschl, E ;

Baumruker, T ;

Hiestand, P ;

Foster, CA ;

Zollinger, M ;

Lynch, KR .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2002, 277 (24) :21453-21457

[7]

DOBROWSKY RT, 1993, J BIOL CHEM, V268, P15523

[8] A novel mechanism for JAK2 activation by a G protein-coupled receptor, the CCK2R - Implication of this signaling pathway in pancreatic tumor models [J].

Ferrand, A ;

Kowalski-Chauvel, A ;

Bertrand, C ;

Escrieut, C ;

Mathieu, A ;

Portolan, G ;

Pradayrol, L ;

Fourmy, D ;

Dufresne, M ;

Seva, C .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2005, 280 (11) :10710-10715

[9]

Ganeshaguru K, 2002, HAEMATOLOGICA, V87, P167

[10]

Goetzl EJ, 1999, J IMMUNOL, V162, P2049

← 1 2 3 4 5 →