A KMT2A-AFF1 gene regulatory network highlights the role of core transcription factors and reveals the regulatory logic of key downstream target genes.
A KMT2A-AFF1 gene regulatory network highlights the role of core transcription factors and reveals the regulatory logic of key downstream target genes.
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DOI：
10.1101/gr.268490.120
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发表时间：
2021-07
期刊：
影响因子：
7
通讯作者：
Milne TA
中科院分区：
文献类型：
--
作者：
Harman JR;Thorne R;Jamilly M;Tapia M;Crump NT;Rice S;Beveridge R;Morrissey E;de Bruijn MFTR;Roberts I;Roy A;Fulga TA;Milne TA
由转录因子（TF）介导的调节相互作用构成了控制细胞行为的复杂网络。充分了解这些基因调控网络（GRNs）提供了更深入的了解致病扰动的后果比可以通过孤立地研究单个TF结合事件。赖氨酸甲基转移酶2A（KMT 2A）基因的染色体易位产生KMT 2A融合蛋白，如KMT 2A-AFF 1（以前称为MLL-AF 4），导致预后不良的急性淋巴细胞白血病（ALL），有时会复发为急性髓性白血病（AML）。KMT 2A-AFF 1通过直接结合并诱导关键基因（如抗凋亡因子BCL 2和原癌基因MYC）的异常过表达来驱动白血病发生。然而，单独研究直接结合并不包括可能的网络生成的调控输出，包括基因阻遏的间接诱导。为了更好地理解KMT 2A-AFF 1驱动的监管格局，我们整合了ChIP-seq、患者RNA-seq和CRISPR必要性筛选，以生成模型GRN。该GRN鉴定了几种关键转录因子，如RUNX 1，其使用前馈环（FFL）和级联基序调节KMT 2A-AFF 1下游的靶基因。一组核心节点存在于ALL和AML中，CRISPR筛选揭示了几个有助于介导对药物venetoclax反应的因素。使用我们的GRN，我们然后鉴定了抑制CASP 9的KMT 2A-AFF 1：RUNX 1级联，以及通过组合TF活性调节BCL 2和MYC的KMT 2A-AFF 1驱动的FFL。这说明了我们的GRN如何用于更好地将KMT 2A-AFF 1行为与有助于白血病发生的下游途径联系起来，并可能预测介导药物反应的基因表达的变化。
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 can be achieved by studying single TF binding events in isolation. Chromosomal translocations of the lysine methyltransferase 2A (KMT2A) gene produce KMT2A fusion proteins such as KMT2A-AFF1 (previously MLL-AF4), causing poor prognosis acute lymphoblastic leukemias (ALLs) that sometimes relapse as acute myeloid leukemias (AMLs). KMT2A-AFF1 drives leukemogenesis through direct binding and inducing the aberrant overexpression of key genes, such as the anti-apoptotic factor BCL2 and the proto-oncogene MYC. However, studying direct binding alone does not incorporate possible network-generated regulatory outputs, including the indirect induction of gene repression. To better understand the KMT2A-AFF1-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 such as RUNX1 that regulate target genes downstream of KMT2A-AFF1 using feed-forward loop (FFL) and cascade motifs. A core set of nodes are present in both ALL and AML, and CRISPR screening revealed several factors that help mediate response to the drug venetoclax. Using our GRN, we then identified a KMT2A-AFF1:RUNX1 cascade that represses CASP9, as well as KMT2A-AFF1-driven FFLs that regulate BCL2 and MYC through combinatorial TF activity. This illustrates how our GRN can be used to better connect KMT2A-AFF1 behavior to downstream pathways that contribute to leukemogenesis, and potentially predict shifts in gene expression that mediate drug response.
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影响因子：
11.8
作者：
Goode DK;Obier N;Vijayabaskar MS;Lie-A-Ling M;Lilly AJ;Hannah R;Lichtinger M;Batta K;Florkowska M;Patel R;Challinor M;Wallace K;Gilmour J;Assi SA;Cauchy P;Hoogenkamp M;Westhead DR;Lacaud G;Kouskoff V;Göttgens B;Bonifer C
通讯作者：
Bonifer C
婴儿MLL重新培养急性淋巴细胞白血病中体细胞突变的景观。
影响因子：
30.8
作者：
Andersson AK;Ma J;Wang J;Chen X;Gedman AL;Dang J;Nakitandwe J;Holmfeldt L;Parker M;Easton J;Huether R;Kriwacki R;Rusch M;Wu G;Li Y;Mulder H;Raimondi S;Pounds S;Kang G;Shi L;Becksfort J;Gupta P;Payne-Turner D;Vadodaria B;Boggs K;Yergeau D;Manne J;Song G;Edmonson M;Nagahawatte P;Wei L;Cheng C;Pei D;Sutton R;Venn NC;Chetcuti A;Rush A;Catchpoole D;Heldrup J;Fioretos T;Lu C;Ding L;Pui CH;Shurtleff S;Mullighan CG;Mardis ER;Wilson RK;Gruber TA;Zhang J;Downing JR;St. Jude Children's Research Hospital–Washington University Pediatric Cancer Genome Project
通讯作者：
St. Jude Children's Research Hospital–Washington University Pediatric Cancer Genome Project
影响因子：
5.2
作者：
Ballabio E;Milne TA
通讯作者：
Milne TA
影响因子：
46.9
作者：
Doench JG;Fusi N;Sullender M;Hegde M;Vaimberg EW;Donovan KF;Smith I;Tothova Z;Wilen C;Orchard R;Virgin HW;Listgarten J;Root DE
通讯作者：
Root DE
影响因子：
16.6
作者：
Crump NT;Ballabio E;Godfrey L;Thorne R;Repapi E;Kerry J;Tapia M;Hua P;Lagerholm C;Filippakopoulos P;Davies JOJ;Milne TA
通讯作者：
Milne TA