MYC-dependent and -independent molecular signatures of I-BET151 antimyeloma activity. (A) Heat map showing the 50 most up- and downregulated genes after treatment with I-BET151 (1 μM) for 6 hours of KMS12BM and H929 cells. HEXIM1 is highlighted by a red asterisk. (B) Venn diagram showing that among the 50 most upregulated genes in I-BET151-treated cells, 10 are shared by the 2 cell lines (left), while among the 50 most downregulated genes, 8 are shared by the 2 cell lines (right). (C) A representative MYC-dependent gene set enriched in both cell lines as determined by GSEA. (D) Venn diagrams showing the number of gene sets significantly enriched (P < .01; FDR q < 0.05) either in both or in individual cell lines. Left: number of gene sets significantly enriched among list of genes upregulated in I-BET151-treated cells; right: number of gene sets enriched among list of genes downregulated in I-BET151-treated cells. MYC-dependent gene sets enriched in the most downregulated genes in response to I-BET151 (shown in purple) form only a minority, with the majority of enriched gene sets being MYC-independent (supplemental Table 1). (E) GSEA analysis reveals enrichment of histone deacetylase (HDAC) inhibitor signatures in both H929 and KMS12BM cell lines (left; only KMS12BM shown here), and a myeloma-specific IRF4-dependent gene set in KMS12BM but not H929 cells (right) upon treatment with I-BET151.