小柯机器人

维持白血病干细胞需要HBO1
2019-12-12 19:39

澳大利亚墨尔本大学Mark A. Dawson研究组发现,HBO1是维持白血病干细胞所需的。 相关论文于2019年12月11日在线发表于国际学术期刊《自然》。

研究人员表示,急性髓细胞性白血病(AML)是一种异质性疾病,其特征在于转录失调,从而导致分化受阻并增加了恶性自我更新。旨在逆转AML这些特征的各种表观遗传疗法已进入临床试验,但由于无法有效根除白血病干细胞(LSC),大多数疗法仅表现出一定的疗效。

为了明确识别LSC中的新依赖性,研究人员筛选了一个小发夹RNA的定制文库,该文库靶向LSC离体小鼠模型中的染色质调节因子。研究人员确定MYST乙酰转移酶HBO1(也称为KAT7或MYST2)和HBO1蛋白复合体的几个已知成员是LSC维持的关键调节因子。

使用CRISPR结构域筛选和定量质谱,研究人员确定了HBO1的组蛋白乙酰转移酶结构域是K14组蛋白H3乙酰化必不可少的。在K14处被H3乙酰化的H3(H3K14ac)促进了RNA聚合酶II的持续合成能力,以维持有助于维持LSC功能特性的关键基因(包括Hoxa9和Hoxa10)的高表达。

为了在治疗上利用这种依赖性,研究人员开发了HBO1的高效小分子抑制剂,并证明了其作为乙酰辅酶A竞争性类似物的活性模式。HBO1的抑制表型拷贝了遗传数据,并显示了对来自患者的多种人类细胞系和原代AML细胞的功效。这些对AML治疗靶标的生物学、结构和化学见解将使这些发现得到临床转化。

附:英文原文

Title: HBO1 is required for the maintenance of leukaemia stem cells

Author: Laura MacPherson, Juliana Anokye, Miriam M. Yeung, Enid Y. N. Lam, Yih-Chih Chan, Chen-Fang Weng, Paul Yeh, Kathy Knezevic, Miriam S. Butler, Annabelle Hoegl, Kah-Lok Chan, Marian L. Burr, Linden J. Gearing, Tracy Willson, Joy Liu, Jarny Choi, Yuqing Yang, Rebecca A. Bilardi, Hendrik Falk, Nghi Nguyen, Paul A. Stupple, Thomas S. Peat, Ming Zhang, Melanie de Silva, Catalina Carrasco-Pozo, Vicky M. Avery, Poh Sim Khoo, Olan Dolezal, Matthew L. Dennis, Stewart Nuttall, Regina Surjadi, Janet Newman, Bin Ren, David J. Leaver, Yuxin Sun, Jonathan B. Baell, Oliver Dovey, George S. Vassiliou, Florian Grebien, Sarah-Jane Dawson, Ian P. Street, Brendon J. Monahan, Christopher J. Burns, Chunaram Choudhary, Marnie E. Blewitt, Anne K. Voss, Tim Thomas, Mark A. Dawson

Issue&Volume: 2019-12-11

Abstract: Acute myeloid leukaemia (AML) is a heterogeneous disease characterized by transcriptional dysregulation that results in a block in differentiation and increased malignant self-renewal. Various epigenetic therapies aimed at reversing these hallmarks of AML have progressed into clinical trials, but most show only modest efficacy owing to an inability to effectively eradicate leukaemia stem cells (LSCs)1. Here, to specifically identify novel dependencies in LSCs, we screened a bespoke library of small hairpin RNAs that target chromatin regulators in a unique ex vivo mouse model of LSCs. We identify the MYST acetyltransferase HBO1 (also known as KAT7 or MYST2) and several known members of the HBO1 protein complex as critical regulators of LSC maintenance. Using CRISPR domain screening and quantitative mass spectrometry, we identified the histone acetyltransferase domain of HBO1 as being essential in the acetylation of histone H3 at K14. H3 acetylated at K14 (H3K14ac) facilitates the processivity of RNA polymerase II to maintain the high expression of key genes (including Hoxa9 and Hoxa10) that help to sustain the functional properties of LSCs. To leverage this dependency therapeutically, we developed a highly potent small-molecule inhibitor of HBO1 and demonstrate its mode of activity as a competitive analogue of acetyl-CoA. Inhibition of HBO1 phenocopied our genetic data and showed efficacy in a broad range of human cell lines and primary AML cells from patients. These biological, structural and chemical insights into a therapeutic target in AML will enable the clinical translation of these findings.

DOI: 10.1038/s41586-019-1835-6

Source: https://www.nature.com/articles/s41586-019-1835-6

Nature:《自然》,创刊于1869年。隶属于施普林格·自然出版集团,最新IF:43.07
官方网址:http://www.nature.com/
投稿链接:http://www.nature.com/authors/submit_manuscript.html


本期文章:《自然》:Online/在线发表

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