Antagonistic activities of the immunomodulator and PP2A-activating drug FTY720 (Fingolimod, Gilenya) in Jak2-driven hematologic malignancies.
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.
Human Cancer Genetics Program, Department of Molecular Virology Immunology and Medical Genetics.
Joshua J
JJ
Oaks
Ramasamy
R
Santhanam
Christopher J
CJ
Walker
Steve
S
Roof
Jason G
JG
Harb
Greg
G
Ferenchak
Ann-Kathrin
AK
Eisfeld
James R
JR
Van Brocklyn
Roger
R
Briesewitz
Sahar A
SA
Saddoughi
Kyosuke
K
Nagata
Robert
R
Bittman
Michael A
MA
Caligiuri
Omar
O
Abdel-Wahab
Ross
R
Levine
Ralph B
RB
Arlinghaus
Alfonso
A
Quintas-Cardama
John M
JM
Goldman
Jane
J
Apperley
Alistair
A
Reid
Dragana
D
Milojkovic
Mark T
MT
Ziolo
Guido
G
Marcucci
Besim
B
Ogretmen
Paolo
P
Neviani
Danilo
D
Perrotti
D000818:Animals; D002461:Cell Line, Transformed; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D058544:Class Ib Phosphatidylinositol 3-Kinase; D004268:DNA-Binding Proteins; D004789:Enzyme Activation / Q000187:drug effects; D000068876:Fingolimod Hydrochloride; D056488:Histone Chaperones; D006801:Humans; D015151:Immunoblotting; D007166:Immunosuppressive Agents / Q000494:pharmacology; D053614:Janus Kinase 2 / Q000235:genetics / Q000378:metabolism*; D053208:Kaplan-Meier Estimate; D007938:Leukemia / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D051379:Mice; D016513:Mice, SCID; D009154:Mutation; D015513:Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D011409:Propylene Glycols / Q000494:pharmacology*; D011493:Protein Kinase C / Q000235:genetics / Q000378:metabolism; D054648:Protein Phosphatase 2 / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D016896:Treatment Outcome
D004268:DNA-Binding Proteins; D056488:Histone Chaperones; D007166:Immunosuppressive Agents; D015513:Oncogene Proteins; D011409:Propylene Glycols; C557500:SET protein, mouse; D058544:Class Ib Phosphatidylinositol 3-Kinase; C546764:Pik3cg protein, mouse; D053614:Janus Kinase 2; D011493:Protein Kinase C; D054648:Protein Phosphatase 2; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine