Next-generation shRNA screen identifies sources of sensitivity and resistance to dex in B-ALL. (A) Venn diagrams showing that 247 of the CRGs are covered by the screen, 63 of which affect dex sensitivity. (B) Volcano plot of the effect of shRNA gene knockdown on dex sensitivity. Each point is a gene with the log significance on the y-axis, with relative effect (phenotype) on dex-induced cell death on the x-axis. GR is the most protective when knocked down, and knockdown of PIK3CD makes NALM-6 cell more sensitive. Top hits (Mann-Whitney, P ≤ .05) are green: sensitizing; purple: protective; gray: P > .05. (C) Zoom of volcano plot showing genes commonly mutated in treatment resistant or relapsed patients with B-ALL have an effect on dex sensitivity when knocked down (supplemental Table 1). (D) Identification of effector genes from among the CRGs. Plot of dex sensitivity phenotype when knocked down (x-axis) vs the average change in expression in response to dex (y-axis) for genes that are significantly regulated by dex and are top hits in the screen. Genes validated as effectors of dex-induced cell death are either: (1) downregulated by dex and cause sensitivity when knocked down (green shaded) or (2) upregulated by dex and are protective when knocked down (purple shaded). Genes involved in B-cell development or previously identified as effectors are in bold.