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<jats:title>ABSTRACT</jats:title><jats:p>Regulatory interactions mediated by transcription factors (TFs) make up complex networks that control cellular behavior. Fully understanding these gene regulatory networks (GRNs) offers greater insight into the consequences of disease-causing perturbations than studying single TF binding events in isolation. Chromosomal translocations of the <jats:italic>Mixed Lineage Leukemia gene</jats:italic> (<jats:italic>MLL</jats:italic>) produce MLL fusion proteins such as MLL-AF4, causing poor prognosis acute lymphoblastic leukemias (ALLs). MLL-AF4 is thought to drive leukemogenesis by directly binding to genes and inducing aberrant overexpression of key gene targets, including anti-apoptotic factors such as BCL-2. However, this model minimizes the potential for circuit generated regulatory outputs, including gene repression. To better understand the MLL-AF4 driven regulatory landscape, we integrated ChIP-seq, patient RNA-seq and CRISPR essentiality screens to generate a model GRN. This GRN identified several key transcription factors, including RUNX1, that regulate target genes using feed-forward loop and cascade motifs. We used CRISPR screening in the presence of the BCL-2 inhibitor venetoclax to identify functional impacts on apoptosis. This identified an MLL-AF4:RUNX1 cascade that represses <jats:italic>CASP9,</jats:italic> perturbation of which disrupts venetoclax induced apoptosis. This illustrates how our GRN can be used to better understand potential mechanisms of drug resistance acquisition.</jats:p><jats:sec><jats:title>Graphical abstract caption</jats:title><jats:fig id="ufig1" position="float" fig-type="figure" orientation="portrait"><jats:caption><jats:p>A network model of the MLL-AF4 regulatory landscape identifies feed-forward loop and cascade motifs. Functional screening using CRISPR and venetoclax identified an MLL-AF4:RUNX1:<jats:italic>CASP9</jats:italic> repressive cascade that impairs drug-induced cell death.</jats:p></jats:caption><jats:graphic xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="179796v1_ufig1" position="float" orientation="portrait" /></jats:fig></jats:sec>

Original publication

DOI

10.1101/2020.06.30.179796

Type

Journal article

Publisher

Cold Spring Harbor Laboratory

Publication Date

02/07/2020