Characterisation of Chromatin Landscapes of Pre-leukaemic and Leukaemic Stem Cells in Core Binding Factor AML and their Response to Epigenetic Therapy

核心结合因子 AML 中白血病前期和白血病干细胞染色质景观的特征及其对表观遗传治疗的反应

• 批准号: MR/P019609/1
• 负责人: Sandeep Potluri
• 金额: $ 30.75万
• 依托单位: University of Birmingham
• 依托单位国家: 英国
• 项目类别: Fellowship
• 财政年份: 2017
• 资助国家: 英国
• 起止时间: 2017 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FP019609%2F1
• 关键词: Characterisation; Chromatin; Landscapes; Pre; leukaemic

Acute Myeloid Leukaemia (AML) is a relatively common blood cancer that forms a significant proportion of my clinical work as a Haematologist. Whilst intensive chemotherapy regimens (which have changed very little since the 1980s(!) can achieve temporary clinical remission in about 80% of patients, 5 year survival is only 15% without going through risky procedures such as a stem cell transplant. Consequently, a key clinical question is to understand on a genomic level what causing all these patients to relapse, with a view to prevention.RUNX1 is a gene that is of utmost importance in blood cell development and has been dubbed in its research community as the "master regulator of blood cell development". We have worked on understanding this gene and its interactions for many years in our group and we have considerable expertise. Mutations in RUNX1 also happen to be one of the commonest defects in AML. We aim to tie our expertise with this gene with the clinical problems of relapse in AML and aim to tackle 4 key objectives:1) Characterise Pre-leukaemic Stem CellsChemotherapy is a rather blunt instrument that kills mainly the fastest-dividing cells. 'Pre-leukaemic stem cells' are blood cells with genetic changes that can eventually give rise to cancer but aren't yet fully cancerous. We propose that these cells are slow-dividing and hence resistant to chemotherapy. They can therefore survive in patients who are apparently in remission and lead to future relapses. We aim to purify pre-leukaemic stem cells from bone marrow of patients with RUNX1 mutations. We will then use state-of-the art technology such as single cell RNA sequencing to understand their biology.2) Improve AML monitoring in RemissionPatients that achieve clinical remission are monitored for relapse by looking at the number of copies of a gene specific to their disease. However we still do not have good markers that would predict relapse. By characterising pre-leukaemic stem cells, this work aims to identify clinically relevant genes targets that can help patients be monitored better.3) Investigate the Role of the Wilms Tumour 1 (WT1) GeneWe already know from the literature that patients that have high levels of the WT1 gene relapse quickly. WT1 has traditionally been thought of by cancer researchers as a gene protective against cancer so we aim to investigate why it harmful in AML. We will perform experiments on cell lines to find out where in the AML genome WT1 acts and other molecules it interacts with. We will also selectively alter levels of the gene in order to determine its role in relapsed leukaemia.4) Investigate Response to Treatment by Epigenetic DrugsAt Birmingham, we have led a phase II clinical trial (RAvVA - currently the largest epigenetic therapies trial of its kind) which recruited 259 patients that were treated with combinations of 2 drugs that alter gene expression - Azacitidine and Vorinostat. However, it is not currently known what exactly these drugs are doing on a genomic level on the AML cells. We aim to elucidate this by comparing changes in gene expression in patients for whom these drugs have benefited compared to those for who they haven't. This can potentially highlight specific genes or signalling pathways to target that might give a more durable clinical response.

急性髓系白血病（AML）是一种相对常见的血液癌症，在我作为血液病学家的临床工作中占很大比例。虽然强化化疗方案（自20世纪80年代以来几乎没有改变）可以在大约80%的患者中实现暂时的临床缓解，5年生存率只有15%，而不需要经历危险的程序，如干细胞移植。因此，一个关键的临床问题是在基因组水平上了解是什么导致所有这些患者复发，以期预防。RUNX 1是一种在血细胞发育中至关重要的基因，在其研究界被称为“血细胞发育的主要调节因子”。多年来，我们一直致力于了解这个基因及其相互作用，我们有相当多的专业知识。RUNX 1突变也是AML中最常见的缺陷之一。我们的目标是将我们对该基因的专业知识与AML复发的临床问题联系起来，并旨在解决4个关键目标：1）表征白血病前干细胞化疗是一种相当钝的工具，主要杀死分裂最快的细胞。“前白血病干细胞”是具有遗传变化的血细胞，最终可能导致癌症，但尚未完全癌变。我们认为这些细胞分裂缓慢，因此对化疗有抵抗力。因此，它们可以在明显缓解的患者中存活，并导致未来复发。我们的目标是从RUNX 1突变患者的骨髓中纯化前白血病干细胞。然后我们将使用最先进的技术，如单细胞RNA测序，以了解他们的生物学。2）改善AML缓解监测达到临床缓解的患者通过观察其疾病特异性基因的拷贝数来监测复发。然而，我们仍然没有很好的标志物来预测复发。通过表征前白血病干细胞，这项工作的目的是确定临床相关的基因靶点，可以帮助患者更好地监测。3）研究Wilms肿瘤1（WT 1）基因的作用我们已经从文献中知道，具有高水平WT 1基因的患者很快复发。WT 1传统上被癌症研究人员认为是一种保护癌症的基因，因此我们的目标是研究为什么它对AML有害。我们将在细胞系上进行实验，以找出WT 1在AML基因组中的作用以及与之相互作用的其他分子。我们还将选择性地改变基因的水平，以确定其在复发性白血病中的作用。4）调查对表观遗传药物治疗的反应在伯明翰，我们已经领导了一项II期临床试验（RAvVA -目前同类中最大的表观遗传疗法试验），该试验招募了259名患者，这些患者接受了2种改变基因表达的药物的组合治疗-阿扎胞苷和伏立诺他。然而，目前尚不清楚这些药物在AML细胞的基因组水平上究竟起什么作用。我们的目标是通过比较这些药物受益的患者与那些没有受益的患者的基因表达变化来阐明这一点。这可能会突出特定的基因或信号通路，从而可能产生更持久的临床反应。

项目成果

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.

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
• 发表时间: 2024
• 期刊: Leukemia
• 影响因子: 11.4
• 作者: Potluri S

Oncogenic gene expression and epigenetic remodeling of cis-regulatory elements in ASXL1-mutant chronic myelomonocytic leukemia.

• DOI: 10.1038/s41467-022-29142-6
• 发表时间: 2022-03-17
• 期刊: Nature communications
• 影响因子: 16.6
• 作者: Binder M;Carr RM;Lasho TL;Finke CM;Mangaonkar AA;Pin CL;Berger KR;Mazzone A;Potluri S;Ordog T;Robertson KD;Marks DL;Fernandez-Zapico ME;Gaspar-Maia A;Patnaik MM
• 通讯作者: Patnaik MM

Invariant NKT cells metabolically adapt to the acute myeloid leukaemia environment.

• DOI: 10.1007/s00262-022-03268-4
• 发表时间: 2023-03
• 期刊: CANCER IMMUNOLOGY IMMUNOTHERAPY
• 影响因子: 5.8
• 作者: Stavrou, Victoria;Fultang, Livingstone;Booth, Sarah;De Simone, Daniele;Bartnik, Arekdiusz;Scarpa, Ugo;Gneo, Luciana;Panetti, Silvia;Potluri, Sandeep;Almowaled, Meaad;Barlow, Jonathan;Jankevics, Andris;Lloyd, Gavin;Southam, Andrew;Priestman, David A.;Cheng, Paul;Dunn, Warwick;Platt, Frances;Endou, Hitoshi;Craddock, Charles;Keeshan, Karen;Mussai, Francis;De Santo, Carmela
• 通讯作者: De Santo, Carmela

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: bioRxiv : the preprint server for biology
• 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,

The Oncogenic Transcription Factor RUNX1/ETO Corrupts Cell Cycle Regulation to Drive Leukemic Transformation.

• DOI: 10.1016/j.ccell.2018.08.015
• 发表时间: 2018-10-08
• 期刊: Cancer cell
• 影响因子: 50.3
• 作者: Martinez-Soria N;McKenzie L;Draper J;Ptasinska A;Issa H;Potluri S;Blair HJ;Pickin A;Isa A;Chin PS;Tirtakusuma R;Coleman D;Nakjang S;Assi S;Forster V;Reza M;Law E;Berry P;Mueller D;Osborne C;Elder A;Bomken SN;Pal D;Allan JM;Veal GJ;Cockerill PN;Wichmann C;Vormoor J;Lacaud G;Bonifer C;Heidenreich O
• 通讯作者: Heidenreich O