Pharmacological inhibition of HDAC relieves epigenetic suppression of BTK-targeting microRNA. (A) HDAC repressor complex inhibits the function of miR-210 and miR-425, causing an upregulation of BTK. BCR ligation induces activation of BTK, promoting CLL cell survival and proliferation. Ibrutinib covalently binds C481 on BTK to inhibit BTK activity and hence inhibit survival and proliferation of CLL cells. (B) Mutation of BTK C481S prevents covalent binding of ibrutinib to BTK and inhibits ibrutinib activity. The HDACi abexinostat releases HDAC1-mediated suppression of miR-210 and miR-425, leading to a decrease in BTK protein expression and suppression of downstream signaling, even in the presence of C481S mutation. Drugs are highlighted in blue and red crosses indicate the pathway is inhibited. BLNK, B-cell linker; LYN, tyrosine-protein kinase Lyn; SYK, spleen tyrosine kinase.