Cotreatment with panobinostat and JAK2 inhibitor TG101209 attenuates JAK2V617F levels and signaling and exerts synergistic cytotoxic effects against human myeloproliferative neoplastic cells

摘要: The mutant JAK2V617F tyrosine kinase (TK) is present in the majority of patients with BCR-ABL–negative myeloproliferative neoplasms (MPNs). activates downstream signaling through signal transducers and activators transcription (STAT), RAS/mitogen-activated protein (MAPK), phosphatidylinositol 3 (PI3)/AKT pathways, conferring proliferative survival advantages MPN hematopoietic progenitor cells (HPCs). Treatment pan-histone deacetylase (HDAC) inhibitor panobinostat (PS) known to inhibit chaperone function heat shock 90, as well induce growth arrest apoptosis transformed HPCs. Here, we demonstrate that PS treatment depletes autophosphorylation, expression, JAK2V617F. also disrupted association hsp90, promoting proteasomal degradation induced cultured JAK2V617F-expressing human erythroleukemia HEL92.1.7 Ba/F3-JAK2V617F cells. JAK2 TK TG101209 attenuated autophosphorylation Cotreatment further depleted JAK/STAT synergistically exerted greater cytotoxicity against primary CD34+ than normal These vitro findings suggest combination therapy HDAC inhibitors potential value for JAK2V617F-positive MPN.