t(8;21) Acute Myeloid Leukemia as a Paradigm for the Understanding of Leukemogenesis at the Level of Gene Regulation and Chromatin Programming.
t(8;21) Acute Myeloid Leukemia as a Paradigm for the Understanding of Leukemogenesis at the Level of Gene Regulation and Chromatin Programming.
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DOI：
10.3390/cells9122681
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发表时间：
2020-12-13
期刊：
影响因子：
6
通讯作者：
Heidenreich O
中科院分区：
文献类型：
--
作者：
Kellaway S;Chin PS;Barneh F;Bonifer C;Heidenreich O
急性髓细胞白血病（AML）是一种异质性疾病，具有多种亚型，这些亚型由不同的体细胞突变定义，这些突变导致血细胞分化误入歧途。突变发生在编码控制转录和染色质结构的细胞机制成员的基因中，包括转录因子、染色质修饰剂、DNA甲基转移酶，以及激活控制基因表达和细胞生长的诱导型转录因子的信号分子。AML患者中的突变细胞无法分化并采用由原始驱动突变形成的新身份，并通过将其基因调控网络重新连接到具有增强适应性的调控表型。研究得最好的AML亚型之一是t（8;21）AML，其携带编码造血主调节因子RUNX 1的DNA结合结构域的易位融合序列至ETO基因。由此产生的癌蛋白RUNX 1/ETO已经在生物化学和系统生物学水平上研究了几十年。它作为RUNX 1的显性阴性版本发挥作用，并干扰与骨髓分化、生长调节和基因组稳定性相关的多种细胞过程。在这篇综述中，我们总结了我们目前对这种蛋白质如何将正常细胞重新编程为恶性细胞的知识，以及我们目前的知识如何被利用来治疗这种疾病。
Acute myeloid leukemia (AML) is a heterogenous disease with multiple sub-types which are defined by different somatic mutations that cause blood cell differentiation to go astray. Mutations occur in genes encoding members of the cellular machinery controlling transcription and chromatin structure, including transcription factors, chromatin modifiers, DNA-methyltransferases, but also signaling molecules that activate inducible transcription factors controlling gene expression and cell growth. Mutant cells in AML patients are unable to differentiate and adopt new identities that are shaped by the original driver mutation and by rewiring their gene regulatory networks into regulatory phenotypes with enhanced fitness. One of the best-studied AML-subtypes is the t(8;21) AML which carries a translocation fusing sequences encoding the DNA-binding domain of the hematopoietic master regulator RUNX1 to the ETO gene. The resulting oncoprotein, RUNX1/ETO has been studied for decades, both at the biochemical but also at the systems biology level. It functions as a dominant-negative version of RUNX1 and interferes with multiple cellular processes associated with myeloid differentiation, growth regulation and genome stability. In this review, we summarize our current knowledge of how this protein reprograms normal into malignant cells and how our current knowledge could be harnessed to treat the disease.
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影响因子：
30.8
作者：
Faber ZJ;Chen X;Gedman AL;Boggs K;Cheng J;Ma J;Radtke I;Chao JR;Walsh MP;Song G;Andersson AK;Dang J;Dong L;Liu Y;Huether R;Cai Z;Mulder H;Wu G;Edmonson M;Rusch M;Qu C;Li Y;Vadodaria B;Wang J;Hedlund E;Cao X;Yergeau D;Nakitandwe J;Pounds SB;Shurtleff S;Fulton RS;Fulton LL;Easton J;Parganas E;Pui CH;Rubnitz JE;Ding L;Mardis ER;Wilson RK;Gruber TA;Mullighan CG;Schlenk RF;Paschka P;Döhner K;Döhner H;Bullinger L;Zhang J;Klco JM;Downing JR
通讯作者：
Downing JR
影响因子：
8
作者：
Frank, RC;Sun, X;Nimer, SD
通讯作者：
Nimer, SD
影响因子：
20.3
作者：
Heidenreich, O;Krauter, J;Nordheim, A
通讯作者：
Nordheim, A
影响因子：
11.4
作者：
Khanna V;Eide CA;Tognon CE;Maxson JE;Wilmot B;Bottomly D;McWeeney S;Edwards V DK;Druker BJ;Tyner JW
通讯作者：
Tyner JW
影响因子：
82.9
作者：
Esposito, Maria Teresa;Zhao, Lu;So, Chi Wai Eric
通讯作者：
So, Chi Wai Eric