Gene regulatory network analysis predicts cooperating transcription factor regulons required for FLT3-ITD+ AML growth.
Gene regulatory network analysis predicts cooperating transcription factor regulons required for FLT3-ITD+ AML growth.
复制标题
基因调控网络分析预测 FLT3-ITD AML 生长所需的协作转录因子调节子。
DOI：
10.1101/2023.07.18.549495
复制
发表时间：
2023
期刊：
影响因子：
--
通讯作者：
Bonifer,
中科院分区：
文献类型：
--
作者：
Coleman,DanielJL;Keane,Peter;Luque-Martin,Rosario;Chin,PaulynnS;Blair,Helen;Ames,Luke;Kellaway,SophieG;Griffin,James;Holmes,Elizabeth;Potluri,Sandeep;Assi,SalamA;Bushweller,John;Heidenreich,Olaf;Cockerill,PeterN;Bonifer,
急性髓系白血病（AML）是由不同突变引起的异质性疾病。以前，我们发现，每个突变亚型发展其特定的基因调控网络（GRN）与转录因子相互作用的多个基因模块，其中许多是转录因子基因本身。在这里，我们假设这些网络中高度连接的节点包括AML维持的关键调节器。我们使用FLT3-ITD突变的AML作为模型来测试这一假设，并通过该分析进行了shRNA脱落筛选。我们发现AML特异性GRNs预测AML生长所需的关键调控模块。此外，我们的工作表明，所有模块都高度连接并相互调节。通过shRNA和化学抑制对一个（RUNX1）模块的作用进行的仔细的多组学分析表明，该转录因子及其靶基因稳定了FLT3-ITD + AML的GRN，并且其去除导致GRN崩溃和细胞死亡。
Acute myeloid leukemia (AML) is a heterogeneous disease caused by different mutations. Previously, we showed that each mutational subtype develops its specific gene regulatory network (GRN) with transcription factors interacting within multiple gene modules, many of which are transcription factor genes themselves. Here, we hypothesize that highly connected nodes within such networks comprise crucial regulators of AML maintenance. We test this hypothesis using FLT3-ITD-mutated AML as a model and conduct an shRNA drop-out screen informed by this analysis. We show that AML-specific GRNs predict crucial regulatory modules required for AML growth. Furthermore, our work shows that all modules are highly connected and regulate each other. The careful multi-omic analysis of the role of one (RUNX1) module by shRNA and chemical inhibition shows that this transcription factor and its target genes stabilize the GRN of FLT3-ITD+ AML and that its removal leads to GRN collapse and cell death.