UM171 exposure elicits a CRL3^KBTBD4-dependent reduction of MYC transcriptional activity. (A) Gene set enrichment analysis showing MYC-associated (upper panel) and TFEB-associated (lower panel) gene signatures in OCI-AML1 cell line after exposure to UM171 (250 nM, 24 hours). (B) Gene set enrichment analysis performed on single-cell RNA sequencing show differentially regulated pathways in CB-derived CD34⁺ subsets after 7 days expansion in presence of UM171 (35 nM) vs vehicle (DMSO). (C) Genome wide CRISPR/CRISPR-associated protein 9 knockout screen identified in addition to RCOR1,² MYC, and its associated regulator CDK9 as synthetic lethal targets of UM171 in OCI-AML1 cell line. (D) Heat map showing transcriptomic expression of MYC (top) and TFEB (bottom) downstream targets upon exposure of DMSO (vehicle), UM134 (inactive analog of UM171, 250 nM), UM171 (250 nM), or LSD1 inhibitor (TCP, 10 μM) in the indicated group (sgAAVS1/shLuc, sgAAVS1/shRCOR1, sgKBTBD4/shLuc, and sgKBTBD4/shRCOR1). See also supplemental Figures 2 and 3. sg, single guide (RNA); sh, short hairpin (RNA).