Finding therapeutic targets in FLT3-ITD AML using a systems biology approach
使用系统生物学方法寻找 FLT3-ITD AML 的治疗靶点
基本信息
- 批准号:MR/S021469/1
- 负责人:
- 金额:$ 168.39万
- 依托单位:
- 依托单位国家:英国
- 项目类别:Research Grant
- 财政年份:2019
- 资助国家:英国
- 起止时间:2019 至 无数据
- 项目状态:已结题
- 来源:
- 关键词:
项目摘要
Leukaemia is a blood cell cancer that arises when stem cells or immature blood cells are hit by a series of mutations in their DNA. The consequence is that the cell starts to activate genes that are not normally active, or genes are altered to make abnormal proteins, or no protein at all. If such a protein is required to switch other genes on or off, the consequences can be devastating. The reason for this is that the finely balanced order in which genes are switched on or off during blood cell development is now disturbed. In the early stages, a single mutation may have little effect, and many apparently normal people already carry some mutations in their blood cells. However, additional mutations create a domino effect. First, some target genes are de-regulated by the mutations. This can lead to stem cells that grow more than they should, but are otherwise quite normal and still can form normal blood cells. Over time additional changes occur that tip the balance from a cell that grows a bit too much, to cells where blood cell development grinds to a halt and the cells become malignant. Such cells do not develop into normal blood cells, but form leukemic cells that keep growing and growing until they finally take over the body. Acute myeloid leukaemia (AML) is the most common acute leukaemia in adults. Despite improvements in supportive care, outcome typically remains poor for older AML patients. It has long been known that AML cannot be classified as just one disease but is highly heterogeneous, involving different genetic mutations and highly variable clinical outcomes. The FLT3-ITD mutation is a growth-promoting mutation, and one of the mutations that has the most devastating effects. It occurs in about 25% of all cases, and generates a continuously active protein that cannot be switched off, which tells cells to grow indefinitely. The clinical prognosis of having such a mutation is dire, and treatment with drugs targeting the FLT3-ITD protein soon results in the development of drug resistance and relapse. The Bonifer/Cockerill group has recently embarked on a series of experiments which highlighted how gene regulation is altered in AML with FLT3-ITD and deviates from normal cells. This was made possible by modern technology that looks at many genes simultaneously. We have uncovered a network of genes which are likely to be essential for the development and maintenance of FLT3-ITD AML. These include the transcriptional regulators RUNX1 and AP-1 which control the abnormal expression of FLT3-ITD AML-specific proteins. We have now teamed up with the Heidenreich lab who developed an in vivo model of human FLT3-ITD AML and the lab of John Bushweller from the University of Virginia who has developed novel drugs that target RUNX1 directly. Our proposed work will build on our results and is designed to (i) identify new targets for therapy, (ii) understand which genes are affected by different drug and (iii) use optimized drugs in mouse models of AMLs to prepare the stage to test these novel molecules in a clinical trial. In this work we will use inhibitory RNA molecules to block the production of proteins that are aberrantly expressed in FLT3-ITD AML. We will use this screen to identify which of the abnormally expressed genes are vital to the growth of these AML cells. Once we have identified genes and pathways that control the gene regulatory network we will use specific reagents and chemical inhibitors to block these points in the AML network, and block leukaemia development. These will include (a) a drug that than specifically block the binding of the DNA-binding transcriptional regulator RUNX1, (b) A shortened version of the FOS protein which acts as a dominantly acting repressor of all members of the AP-1 family of transcriptional regulators, and (3) combinations of clinically approved inhibitors of FLT3-ITD and MAPK signalling, which we predict will be more effective than therapies using single agents.
白血病是一种血细胞癌症,当干细胞或未成熟的血细胞被其DNA中的一系列突变击中时发生。结果是细胞开始激活通常不活跃的基因,或者基因被改变以产生异常蛋白质,或者根本没有蛋白质。如果这种蛋白质需要打开或关闭其他基因,后果可能是毁灭性的。其原因是,在血细胞发育过程中,基因开启或关闭的精细平衡顺序现在被打乱了。在早期阶段,单个突变可能影响不大,许多明显正常的人已经在他们的血细胞中携带了一些突变。然而,额外的突变会产生多米诺骨牌效应。首先,一些靶基因被突变解除调控。这可能导致干细胞比它们应该生长的更多,但在其他方面非常正常,仍然可以形成正常的血细胞。随着时间的推移,会发生额外的变化,从生长过多的细胞到血细胞发育停止的细胞,细胞变得恶性。这些细胞不会发育成正常的血细胞,而是形成白血病细胞,这些细胞不断生长,直到最终接管身体。急性髓性白血病(AML)是成人中最常见的急性白血病。尽管支持性治疗有所改善,但老年AML患者的结局通常仍然很差。人们早就知道,AML不能被归类为一种疾病,而是高度异质性的,涉及不同的基因突变和高度可变的临床结果。FLT 3-ITD突变是一种促进生长的突变,也是具有最具破坏性影响的突变之一。它发生在大约25%的病例中,并产生一种无法关闭的持续活性蛋白质,它告诉细胞无限生长。具有这种突变的临床预后是可怕的,并且用靶向FLT 3-ITD蛋白的药物治疗很快导致耐药性和复发的发展。Bonifer/Cockerill小组最近开始了一系列实验,这些实验强调了FLT 3-ITD AML中的基因调控是如何改变的,并偏离了正常细胞。这是通过同时观察许多基因的现代技术实现的。我们已经发现了一个基因网络,这些基因可能对FLT 3-ITD AML的发展和维持至关重要。这些包括转录调节因子RUNX 1和AP-1,它们控制FLT 3-ITD AML特异性蛋白的异常表达。我们现在已经与Heidenreich实验室合作,该实验室开发了人类FLT 3-ITD AML的体内模型,以及弗吉尼亚大学的John Bushweller实验室,该实验室开发了直接靶向RUNX 1的新药。我们提出的工作将建立在我们的研究结果的基础上,旨在(i)确定新的治疗靶点,(ii)了解哪些基因受到不同药物的影响,以及(iii)在AML小鼠模型中使用优化的药物,为在临床试验中测试这些新分子做好准备。在这项工作中,我们将使用抑制性RNA分子来阻断FLT 3-ITD AML中异常表达的蛋白质的产生。我们将使用这种筛选来确定哪些异常表达的基因对这些AML细胞的生长至关重要。一旦我们确定了控制基因调控网络的基因和途径,我们将使用特定的试剂和化学抑制剂来阻断AML网络中的这些点,并阻断白血病的发展。这些将包括(a)特异性阻断DNA结合转录调节因子RUNX 1结合的药物,(B)FOS蛋白的缩短形式,其作为转录调节因子的AP-1家族所有成员的显性作用阻遏物,和(3)临床批准的FLT 3-ITD和MAPK信号传导抑制剂的组合,我们预测这将比使用单一药物的治疗更有效。
项目成果
期刊论文数量(10)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Gene regulatory network analysis predicts cooperating transcription factor regulons required for FLT3-ITD+ AML growth.
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
- 发表时间:2023
- 期刊:
- 影响因子:0
- 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,
- 通讯作者:Bonifer,
A genome-wide relay of signalling-responsive enhancers drives hematopoietic specification.
- DOI:10.1038/s41467-023-35910-9
- 发表时间:2023-01-17
- 期刊:
- 影响因子:16.6
- 作者:Edginton-White, B.;Maytum, A.;Kellaway, S. G.;Goode, D. K.;Keane, P.;Pagnuco, I.;Assi, S. A.;Ames, L.;Clarke, M.;Cockerill, P. N.;Gottgens, B.;Cazier, J. B.;Bonifer, C.
- 通讯作者:Bonifer, C.
Modelling t(8;21) acute myeloid leukaemia - What have we learned?
- DOI:10.1002/mco2.30
- 发表时间:2020-12
- 期刊:
- 影响因子:9.9
- 作者:Chin PS;Bonifer C
- 通讯作者:Bonifer C
Leukemic stem cells hijack lineage inappropriate signalling pathways to promote their growth
- DOI:10.1101/2023.03.10.532081
- 发表时间:2023-04
- 期刊:
- 影响因子:0
- 作者:S. Kellaway;S. Potluri;P. Keane;H. Blair;P. Chin;A. Ptasinska;Alice Worker;L. Ames;Assunta Adamo;D. Coleman;Naeem Khan;Salam A. Assi;A. Krippner-Heidenreich;M. Raghavan;P. Cockerill;O. Heidenreich;C. Bonifer
- 通讯作者:S. Kellaway;S. Potluri;P. Keane;H. Blair;P. Chin;A. Ptasinska;Alice Worker;L. Ames;Assunta Adamo;D. Coleman;Naeem Khan;Salam A. Assi;A. Krippner-Heidenreich;M. Raghavan;P. Cockerill;O. Heidenreich;C. Bonifer
t(8;21) Acute Myeloid Leukemia as a Paradigm for the Understanding of Leukemogenesis at the Level of Gene Regulation and Chromatin Programming.
- DOI:10.3390/cells9122681
- 发表时间:2020-12-13
- 期刊:
- 影响因子:6
- 作者:Kellaway S;Chin PS;Barneh F;Bonifer C;Heidenreich O
- 通讯作者:Heidenreich O
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Constanze Bonifer其他文献
3113 – LEUKAEMIC STEM CELLS CELL HIJACK LINEAGE INAPPROPRIATE SIGNALLING PATHWAYS TO ACTIVATE GROWTH
- DOI:
10.1016/j.exphem.2022.07.169 - 发表时间:
2022-01-01 - 期刊:
- 影响因子:
- 作者:
Sophie Kellaway;Sandeep Potluri;Luke Ames;Peter Keane;Paulynn Chin;Anetta Ptasinska;Salam Assi;Alice Worker;Helen Blair;Olaf Heidenreich;Peter Cockerill;Constanze Bonifer - 通讯作者:
Constanze Bonifer
Declined presentation the pattern of aberrant chromatin programming in acute myeloid leukemia is determined by the mutational landscape
- DOI:
10.1016/j.exphem.2017.06.308 - 发表时间:
2017-09-01 - 期刊:
- 影响因子:
- 作者:
Constanze Bonifer;Ching Ting Justin Loke;Salam Assi;Maria Rosaria Imperato;Anetta Ptasinska;Anna Pickin;Pierre Cauchy;Natalja Martinez-Soria;Paulynn Chin;Olaf Heidenreich;Peter Cockerill - 通讯作者:
Peter Cockerill
Integrated analyses of chromatin accessibility and gene expression data for elucidating the transcriptional regulatory mechanisms during early hematopoietic development in mouse
- DOI:
10.1186/1756-8935-6-s1-p50 - 发表时间:
2013-03-01 - 期刊:
- 影响因子:3.500
- 作者:
Mahalingam S Viiavabaskar;Nadine Obier;Stella Pearson;Maarten Hoogenkamp;Monika Lichtinger;Georges Lacaud;Valerie Kouskoff;Bertie Gottgens;Constanze Bonifer;David R Westhead - 通讯作者:
David R Westhead
Identification of a dynamic core transcriptional regulatory network for t(8;21) AML
- DOI:
10.1016/j.exphem.2013.05.061 - 发表时间:
2013-08-01 - 期刊:
- 影响因子:
- 作者:
Anetta Ptasinska;Salam Assi;Dan Williamson;Pierre Cauchy;Daniel Tenen;Peter Cockerill;David Westhead;Olaf Heidenreich;Constanze Bonifer - 通讯作者:
Constanze Bonifer
3075 - Phenotypic and Transcriptomic Analysis of the Disruption of Embryonic Hematopoietic Development by A Panel of RUNX1 Mutants
- DOI:
10.1016/j.exphem.2018.06.261 - 发表时间:
2018-08-01 - 期刊:
- 影响因子:
- 作者:
Sophie Kellaway;Regha Kakkad;Peter Keane;Salam Assi;Constanze Bonifer - 通讯作者:
Constanze Bonifer
Constanze Bonifer的其他文献
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{{ truncateString('Constanze Bonifer', 18)}}的其他基金
UNDERSTANDING THE INTERPLAY OF ENHANCERS, CHROMATIN PRIMING ELEMENTS AND SIGNALS REGULATING DYNAMIC GENE EXPRESSION IN DEVELOPMENT
了解增强子、染色质启动元件和发育过程中动态基因表达调节信号的相互作用
- 批准号:
BB/R014809/1 - 财政年份:2018
- 资助金额:
$ 168.39万 - 项目类别:
Research Grant
MECHANISTIC INSIGHTS INTO THE DEVELOPMENTAL-STAGE SPECIFIC ACTIVITY OF A UBIQUITOUSLY EXPRESSED TRANSCRIPTION FACTOR
对普遍表达的转录因子的发育阶段特异性活性的机制见解
- 批准号:
BB/M020800/1 - 财政年份:2015
- 资助金额:
$ 168.39万 - 项目类别:
Research Grant
Establishment of the haemopoietic transcriptional programme: From systems approaches to molecular mechanisms
造血转录程序的建立:从系统方法到分子机制
- 批准号:
BB/I001220/2 - 财政年份:2011
- 资助金额:
$ 168.39万 - 项目类别:
Research Grant
The role of the transcription factor Sp1 in embryonic macrophage development
转录因子Sp1在胚胎巨噬细胞发育中的作用
- 批准号:
G0901579/2 - 财政年份:2011
- 资助金额:
$ 168.39万 - 项目类别:
Research Grant
Establishment of the haemopoietic transcriptional programme: From systems approaches to molecular mechanisms
造血转录程序的建立:从系统方法到分子机制
- 批准号:
BB/I001220/1 - 财政年份:2011
- 资助金额:
$ 168.39万 - 项目类别:
Research Grant
The role of the transcription factor Sp1 in embryonic macrophage development
转录因子Sp1在胚胎巨噬细胞发育中的作用
- 批准号:
G0901579/1 - 财政年份:2010
- 资助金额:
$ 168.39万 - 项目类别:
Research Grant
Developing methods and bioinformatics tools for the global analysis of accessible regions in chromatin
开发用于染色质可及区域全局分析的方法和生物信息学工具
- 批准号:
BB/F02441X/1 - 财政年份:2008
- 资助金额:
$ 168.39万 - 项目类别:
Research Grant
Mechanistic insights into priming and early gene activation processes in the haemopoietic system
对造血系统启动和早期基因激活过程的机制见解
- 批准号:
BB/E025129/1 - 财政年份:2008
- 资助金额:
$ 168.39万 - 项目类别:
Research Grant
Improving the specificity and throughput of automated analysis of chromatin fine structure in eukaryotic cells
提高真核细胞染色质精细结构自动分析的特异性和通量
- 批准号:
BB/E005640/1 - 财政年份:2006
- 资助金额:
$ 168.39万 - 项目类别:
Research Grant
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