Cotreatment with panobinostat and JAK2 inhibitor TG101209 attenuates JAK2V617F levels and signaling and exerts synergistic cytotoxic effects against human myeloproliferative neoplastic cells.
The mutant JAK2V617F tyrosine kinase (TK) is present in the majority of patients with BCR-ABL-negative myeloproliferative neoplasms (MPNs). JAK2V617F activates downstream signaling through the signal transducers and activators of transcription (STAT), RAS/mitogen-activated protein kinase (MAPK), and phosphatidylinositol 3 (PI3)/AKT pathways, conferring proliferative and survival advantages in the MPN hematopoietic progenitor cells (HPCs). Treatment with the pan-histone deacetylase (HDAC) inhibitor panobinostat (PS) is known to inhibit the chaperone function of heat shock protein 90, as well as induce growth arrest and apoptosis of transformed HPCs. Here, we demonstrate that PS treatment depletes the autophosphorylation, expression, and downstream signaling of JAK2V617F. Treatment with PS also disrupted the chaperone association of JAK2V617F with hsp90, promoting proteasomal degradation of JAK2V617F. PS also induced apoptosis of the cultured JAK2V617F-expressing human erythroleukemia HEL92.1.7 and Ba/F3-JAK2V617F cells. Treatment with the JAK2 TK inhibitor TG101209 attenuated JAK2V617F autophosphorylation and induced apoptosis of HEL92.1.7 and Ba/F3-JAK2V617F cells. Cotreatment with PS and TG101209 further depleted JAK/STAT signaling and synergistically induced apoptosis of HEL92.1.7 and Ba/F3-JAK2V617F cells. Cotreatment with TG101209 and PS exerted greater cytotoxicity against primary CD34(+) MPN cells than normal CD34(+) HPCs. These in vitro findings suggest combination therapy with HDAC and JAK2V617F inhibitors is of potential value for the treatment of JAK2V617F-positive MPN.
Wang
Yongchao
Y
Medical College of Georgia Cancer Center, Augusta, GA 30912, USA.
Fiskus
Warren
W
Chong
Daniel G
DG
Buckley
Kathleen M
KM
Natarajan
Kavita
K
Rao
Rekha
R
Joshi
Atul
A
Balusu
Ramesh
R
Koul
Sanjay
S
Chen
Jianguang
J
Savoie
Andrew
A
Ustun
Celalettin
C
Jillella
Anand P
AP
Atadja
Peter
P
Levine
Ross L
RL
Bhalla
Kapil N
KN
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D017209:Apoptosis; D015153:Blotting, Western; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000008:administration & dosage; D015870:Gene Expression / Q000187:drug effects; D006412:Hematopoietic Stem Cells / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000008:administration & dosage; D047468:Immunoprecipitation; D007211:Indoles; D053614:Janus Kinase 2 / Q000378:metabolism; D008232:Lymphoproliferative Disorders / Q000188:drug therapy*; D051379:Mice; D000077767:Panobinostat; D010766:Phosphorylation; D016133:Polymerase Chain Reaction; D011743:Pyrimidines / Q000008:administration & dosage; D015398:Signal Transduction / Q000187:drug effects*; D013449:Sulfonamides / Q000008:administration & dosage; D000096926:Benzenesulfonamides
D004791:Enzyme Inhibitors; D006877:Hydroxamic Acids; D007211:Indoles; D053614:Janus Kinase 2; D000077767:Panobinostat; D011743:Pyrimidines; D013449:Sulfonamides; C522865:TG101209; D000096926:Benzenesulfonamides; C507924:JAK2 protein, human