BTK inhibition and BTK degradation have comparable effects on CLL biology. (A) In vitro assays using CLL PBMCs to investigate the impact of different drugs on BTK-dependent signaling in response to BCR engagement. (B) CLL cell transcriptome assessed by RNA sequencing of CLL cells from 4 patients treated with DMSO, hook, 1 μM ibrutinib (IBR), or 2 nM NRX-0492, DMSO for 18 hours followed by 20 μg/mL anti-IgM stimulation for 6 hours. Median centered heatmap scaled as indicated depicts changes in defined gene signatures representing MYC, BCR, and NF-κB regulated genes. Each row represents a gene and each column represents a sample. supplemental Table 2 lists the genes in the same sequence as shown in the heat map together with the expression value across the different conditions. (C) Histogram depicting flow cytometry staining of p-ERK1/2^{Thr202/Tyr204} in CLL cells from 2 representative patients, drug treatment as in B, anti-IgM stimulation for 15 minutes. (D) CCL3 and (E) CCL4 concentrations by enzyme-linked immunosorbent assay in supernatant of CLL cells treated as in B, cell culture supernatants collected 48 hours after stimulation. ERK, extracellular signal-regulated kinase.