Gene regulation in t(6;9) DEK::NUP214 Acute Myeloid Leukemia resembles that of FLT3-ITD/NPM1 Acute Myeloid Leukemia but with an altered HOX/MEIS axis.
Gene regulation in t(6;9) DEK::NUP214 Acute Myeloid Leukemia resembles that of FLT3-ITD/NPM1 Acute Myeloid Leukemia but with an altered HOX/MEIS axis.
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t(6;9) DEK::NUP214 急性髓系白血病的基因调控类似于 FLT3-ITD/NPM1 急性髓系白血病，但 HOX/MEIS 轴发生改变。
DOI：
10.1038/s41375-023-02118-1
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发表时间：
2024
期刊：
影响因子：
11.4
通讯作者：
Potluri S
中科院分区：
文献类型：
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作者：
Potluri S
急性髓系白血病(AML)是一组异质性的血液系统恶性肿瘤。在1%的AML中发现t(6；9)(p23；q34)易位，产生dek：：NUP214融合蛋白。它会导致一种高度侵袭性的疾病，在平均年龄只有23岁的患者中预后很差[1]。T(6；9)AML通常也含有Flt3内部串联重复(ITD)突变，这也是造成不良结果的原因[1]。AML分化和增殖中断的不同机制对治疗改进提出了挑战，因为每种AML亚型都形成了自己的基因调控网络(GRN)，这依赖于驱动突变，这与健康细胞不同[2]。GRN强调哪些转录因子(TF)在哪些水平上调节哪些基因，并告知特定的脆弱性[2]。尽管存在不同的致癌基因，t(6；9)AML的基因表达模式与NPM1突变和NUP98：：NSD1 AML[3，4]相似。然而，由于GRN尚未被研究，目前尚不清楚DEK：：NUP214如何下调AML中的基因表达[5，6]。在健康的造血细胞中，DEK是一种DNA和RNA结合蛋白，具有不同的功能，包括调节染色质可及性和组蛋白乙酰化[6]。NUP214是核孔复合体的一部分，在细胞周期进程和核质运输等多个途径中发挥作用[5]。DEK：：NUP214被认为扰乱了各种核过程，导致髓系分化的失调[6]。这包括解除对HOX基因簇的调控，HOX基因簇编码在正常造血发育中起关键作用的一系列转录因子，它们是受到严格调控的时空表达模式，是正常造血分化所必需的[7]。HOX基因的异常激活与多种AML亚型的白血病发生有关，包括t(6；9)[3，4，7，8]。在这里，我们利用全基因组染色质的可及性来阐明正常的造血祖细胞GRN是如何被DEK：：NUP214干扰的。我们发现DEK：：NUP214 AML GRN与突变体NPM1 AML的DEK：：NUP214 AML GRN相关，但也显示了一个
Acute Myeloid Leukemia (AML) represents a heterogeneous group of hematological malignancies. The t (6; 9)(p23; q34) translocation, generating the DEK:: NUP214 fusion protein is found in 1% of AML. It causes a highly aggressive disease with poor prognosis in patients with a median age of just 23 [1]. t (6; 9) AML often harbours a FLT3 internal tandem duplication (ITD) mutation as well which contributes to adverse outcomes [1]. Differing mechanisms underlying disrupted differentiation and proliferation in AML challenge treatment improvement, as each AML subtype forms its own gene regulatory network (GRN) dependent on the driver mutation, which is distinct from healthy cells [2]. GRNs highlight which transcription factors (TFs) regulate which genes at which level, and inform on specific vulnerabilities [2]. Despite harbouring different driver oncogenes, gene expression patterns of t (6; 9) AML resemble those of NPM1-mutated and NUP98:: NSD1 AML [3, 4]. However, it remains unclear how DEK:: NUP214 de-regulates gene expression in AML as the GRN has not been studied [5, 6].In healthy hematopoietic cells, DEK is a DNA and RNA binding protein with different functions including modulating chromatin accessibility and histone acetylation [6]. NUP214 is a part of the nuclear pore complex, with roles in multiple pathways such as cell cycle progression and nucleocytoplasmic transport [5]. DEK:: NUP214 is thought to disrupt various nuclear processes leading to the dysregulation of myeloid differentiation [6]. This includes deregulation of HOX gene clusters, which encode a family of TFs with crucial roles in normal hematopoietic development and which are tightly regulated display spatial-temporal expression patterns and are required for normal haematopoietic differentiation [7]. Aberrant activation of HOX genes has been associated with leukemogenesis in multiple AML sub-types, including t (6; 9)[3, 4, 7, 8]. Here, we utilise genome-wide chromatin accessibility to elucidate how the normal haematopoietic progenitor cell GRN is disrupted by DEK:: NUP214. We find that the DEK:: NUP214 AML GRN is related to that of mutant NPM1 AML, but also displays an