Fig. 1: CDK12 is synthetic lethal with Myc activation.

a Dot plot of the normalized differential DDR score (y axis, Z-score for DDR) and the normalized differential viability (x axis, Z-score for viability) for each siRNA of the library targeting druggable genes (primary screen). A positive Z-score for DDR indicates higher DDR upon MycER activation compared to mock activated U2OS-MycER cells, while a negative viability Z-score indicates a reduction of viability compared to mock activated cells. Dashed lines indicate thresholds used to call the DDR and viability hits. b Venn diagram of all the hits identified in the two primary screens as DDR- and viability-hits. c Metascape enrichment network of the hits of the two primary screens (DDR and druggable genes). d Cell death in U2OS-MycER cells upon MycER activation (+OHT, 400 nM) and CDK12 knockdown by the indicated shRNAs. e, f WB analysis of DDR markers in U2OS-MycER cells upon MycER activation (+OHT, 400 nM) and (e) CDK12 knockdown or (f) CDK12 inhibition by THZ531. g WB analysis of DDR markers following treatment of multiple myeloma (KMS-11, OPM1) and Burkitt’s lymphoma (Raji, BL28) cell lines with THZ531 for 48 hours. Vinculin (VCL) was used as loading control. Lanes 1, 2, and 3 show independent replicates.