Targeting BTK through microRNA in chronic lymphocytic leukemia

Abstract

Key Points• Inhibition of HDAC reverses epigenetic silencing to upregulate miRs that target BTK and suppress its downstream prosurvival signaling.• We identified a rationale for the dual targeting of BTK when combined with ibrutinib and a strategy to eliminate the C481S-mutant BTK clone.Bruton's tyrosine kinase (BTK) is a critical mediator of survival in B-cell neoplasms. Although BTK inhibitors have transformed therapy in chronic lymphocytic leukemia (CLL), patients with high-risk genetics are at risk for relapse and have a poor prognosis. Identification of novel therapeutic strategies for this group of patients is an urgent unmet clinical need, and therapies that target BTK via alternative mechanisms may fill this niche. Herein, we identify a set of microRNAs (miRs) that target BTK in primary CLL cells and show that the histone deacetylase (HDAC) repressor complex is recruited to these miR promoters to silence their expression. Targeting the HDACs by using either RNA interference against HDAC1 in CLL or a small molecule inhibitor (HDACi) in CLL and mantle cell lymphoma restored the expression of the BTK-targeting miRs with loss of BTK protein and downstream signaling and consequent cell death. We have also made the novel and clinically relevant discovery that inhibition of HDAC induces the BTK-targeting miRs in ibrutinib-sensitive and resistant CLL to effectively reduce both wild-type and C481S-mutant BTK. This finding identifies a novel strategy that may be promising as a therapeutic modality to eliminate the C481S-mutant BTK clone that drives resistance to ibrutinib and provides the rationale for a combination strategy that includes ibrutinib to dually target BTK to suppress its prosurvival signaling. (Blood. 2016;128(26):3101-3112)

Human Mast Cell Sensitization with IgE Increases miRNA-210 Expression

“…Thus, it is plausible that these miRNAs could be involved in FcεRI-mediated MC activation affecting NRTK signaling transduction though PI3K-AKT and MAPK signaling before MC degranulation and interleukin/cytokine generation. Furthermore, the BTK gene is a direct target of miR-210 [12]. In line with this, miR-210 has previously been shown to increase expression of interleukin (IL)-1a and tumor necrosis factor (TNF)-α in HL1 cardiomyocytes [13].…”

How I manage ibrutinib-refractory chronic lymphocytic leukemia

“…36 HDAC inhibitors have been shown to inhibit BTK protein expression through upregulation of BTK-targeting microRNAs and show cytotoxicity and signaling inhibition in cells with C481S BTK. 37 Similarly, the XPO1/CRM1 inhibitor selinexor has been shown to suppress BTK gene expression and to be effective in cell lines with BTK C481S mutations, as well as an in vivo model of ibrutinib resistance. 38 Certainly there are other agents and pathways with the potential for utility in this group of patients, and further study is needed to identify promising targets.…”

Mechanisms of Acquired Drug Resistance to the HDAC6 Selective Inhibitor Ricolinostat Reveals Rational Drug-Drug Combination with Ibrutinib

“…Recent publications have established other links with HDACs and signaling of the BTK pathway. HDAC inhibition has been shown to restore the expression of BTK-targeting miRNA, leading to decreased signaling of the BTK pathway and ultimately apoptosis [28]. Combinations of panobinostat or abexinostat with ibrutinib were synergistic and overcame BTK mutations known to induce ibrutinib resistance.…”