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

   

Authors:	Oaks, J. J.; Santhanam, R.; Walker, C. J.; Roof, S.; Harb, J. G.; Ferenchak, G.; Eisfeld, A. K.; Van Brocklyn, J. R.; Briesewitz, R.; Saddoughi, S. A.; Nagata, K.; Bittman, R.; Caligiuri, M. A.; Abdel-Wahab, O.; Levine, R.; Arlinghaus, R. B.; Quintas-Cardama, A.; Goldman, J. M.; Apperley, J.; Reid, A.; Milojkovic, D.; Ziolo, M. T.; Marcucci, G.; Ogretmen, B.; Neviani, P.; Perrotti, D.
Article Title:	Antagonistic activities of the immunomodulator and PP2A-activating drug FTY720 (Fingolimod, Gilenya) in Jak2-driven hematologic malignancies
Abstract:	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-3Kγ-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-3Kγ-PKC-SET-mediated PP2A inhibition. Thus, PADs (eg, FTY720) represent suitable therapeutic alternatives for Jak2(V617F) MPNs.
Keywords:	signal transduction; treatment outcome; leukemia; oncoprotein; genetics; mutation; janus kinase 2; mouse; animal; metabolism; animals; mice; cells, cultured; reverse transcription polymerase chain reaction; cell line; rna interference; enzyme activation; drug effect; pathology; mice, scid; cell line, tumor; cell culture; reverse transcriptase polymerase chain reaction; oncogene proteins; tumor cell line; drug derivative; immunoblotting; cell line, transformed; protein kinase c; kaplan meier method; sphingosine; immunosuppressive agents; scid mouse; immunosuppressive agent; kaplan-meier estimate; protein phosphatase 2; phosphoprotein phosphatase 2; phosphatidylinositol 4,5 bisphosphate 3 kinase; humans; human; article; fingolimod; pik3cg protein, mouse; propanediol derivative; set protein, mouse; class ib phosphatidylinositol 3-kinase; propylene glycols
Journal Title:	Blood
Volume:	122
Issue:	11
ISSN:	0006-4971
Publisher:	American Society of Hematology
Date Published:	2013-09-12
Start Page:	1923
End Page:	1934
Language:	English
DOI:	10.1182/blood-2013-03-492181
PUBMED:	23926298
PROVIDER:	scopus
PMCID:	PMC3772499
DOI/URL:	http://www.scopus.com/inward/record.url?eid=2-s2.0-84887391984&partnerID=40&md5=c027a8df8c28c7c470e2850976b45205
Notes:	Cited By (since 1996):1 -- Export Date: 9 May 2014 -- Source: Scopus

https://synapse.mskcc.org/synapse/works/has_related_data_chk/49148