Highlights d Development of YKL-5-124 a potent, selective and covalent CDK7 inhibitor d Selective CDK7 inhibition results in cell-cycle inhibition rather than apoptosis d YKL-5-124 exhibited little effect on RNA polymerase II phosphorylation status

Summary Epicuticular waxes provide a hydrophobic barrier that protects land plants from environmental stresses. To elucidate the molecular functions of maize glossy mutants that reduce the accumulation of epicuticular waxes, eight non‐allelic glossy mutants were subjected to transcriptomic comparisons with their respective wild‐type siblings. Transcriptomic comparisons identified 2279 differentially expressed (DE) genes. Other glossy genes tended to be down‐regulated in glossy mutants; by contrast stress‐responsive pathways were induced in mutants. Gene co‐expression network (GCN) analysis found that glossy genes were clustered, suggestive of co‐regulation. Genes that potentially regulate the accumulation of glossy gene transcripts were identified via a pathway level co‐expression analysis. Expression data from diverse organs showed that maize glossy genes are generally active in young leaves, silks, and tassels, while largely inactive in seeds and roots. Through reverse genetics, a DE gene homologous to Arabidopsis CER8 and co‐expressed with known glossy genes was confirmed to participate in epicuticular wax accumulation. GCN data‐informed forward genetics approach enabled cloning of the gl14 gene, which encodes a putative membrane‐associated protein. Our results deepen understanding of the transcriptional regulation of the genes involved in the accumulation of epicuticular wax, and provide two maize glossy genes and a number of candidate genes for further characterization.

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Somatic mutations are rare in pediatric AML (pAML), indicating alternate strategies are needed to identify targetable dependencies. We performed the first enhancer mapping of 3 pAML in 22 patient samples. Generally, pAML samples were distinct from adult AML 4 samples, and MLL (KMT2A)-rearranged samples were also distinct from non-KMT2A-5 rearranged samples. Focusing specifically on super-enhancers (SEs), we identified SEs 6 associated with many known leukemia regulators. The retinoic acid receptor alpha 7 (RARA) gene was differentially regulated in our cohort, and a RARA associated SE was 8 detected in 64% our cohort across all cyto/molecular subtypes tested. RARA SE-positive 9 pAML cell lines and samples demonstrated high RARA mRNA levels. These samples 10 were specifically sensitive to the synthetic RARA agonist tamibarotene in vitro, with 11 slowed proliferation, apoptosis induction, differentiation, and upregulated retinoid target 12 gene expression, compared to RARA SE-negative samples. Tamibarotene prolonged 13 survival and suppressed the leukemia burden of a RARA SE-positive pAML patient-14 derived xenograft (PDX) mouse model compared to a RARA SE-negative PDX. Our work 15 demonstrates that examining chromatin regulation can identify new, druggable 16 dependencies in pAML and provides rationale for a pediatric tamibarotene trial in children 17 with RARA-high AML.

Long noncoding RNAs (lncRNA) can drive tumorigenesis and are susceptible to therapeutic intervention. Here, we used a large-scale CRISPR interference viability screen to interrogate cell growth dependency to lncRNA genes in multiple myeloma (MM), and identified a prominent role for the miR-17-92 cluster host gene (MIR17HG). We show that a MIR17HG-derived lncRNA, named lnc-17-92, is the main mediator of cell growth dependency acting in a microRNA- and DROSHA- independent manner. Lnc-17-92 provides a chromatin scaffold for the functional interaction between c-MYC and WDR82, thus promoting the expression of ACACA, which encodes the rate-limiting enzyme of de novo lipogenesis acetyl-coA carboxylase 1 (ACC1). Targeting MIR17HG pre-RNA with clinically applicable antisense molecules disrupts the transcriptional and functional activities of lnc-17-92, causing potent anti-tumor effects both in vitro and in vivo in three pre-clinical animal models, including a clinically relevant PDX-NSG mouse model. This study establishes a novel oncogenic function of MIR17HG and provides potent inhibitors for translation to clinical trials.