Epigenetic Control of Gene Expression in Leukaemia and Haematopoiesis

白血病和造血中基因表达的表观遗传控制

• 批准号: MC_UU_00029/6
• 负责人: Tom Milne
• 金额: $ 250.76万
• 依托单位: University of Oxford
• 依托单位国家: 英国
• 项目类别: Intramural
• 财政年份: 2022
• 资助国家: 英国
• 起止时间: 2022 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MC_UU_00029%2F6
• 关键词: Epigenetic; Control; Gene; Expression; Leukaemia

Acute lymphoblastic leukaemia (ALL) in children used to be a disease that was untreatable. Thankfully, general care for ALL has greatly improved so that ~90% of children are cured. Unfortunately, there are still rare subsets of ALL that have a tendency to relapse and are untreatable. We are trying to understand the molecular details of these rare, incurable ALLs in order to design new therapies. In order to do this, we study how epigenetics impacts gene regulation. Genes are made up DNA, and they reside in the nucleus, where they act as hardware for the cell that needs to be "read" in order to be functional. When genes are read (or what we call "activated")inappropriately, this can cause aberrant behaviour such as cancerous growth. Epigenetics is information that is not stored directly in the DNA itself. For example, some epigenetic information is stored in chemical modifications carried by histone proteins that interact with DNA in a structure called chromatin. It is becoming clear not only that aberrant epigenetic changes are common in many human diseases such as leukaemia, but that these changes by their very nature are reversible. Our goal is to help design therapies that can target these reversible epigenetic changes.

儿童急性淋巴细胞性白血病(ALL)过去是一种无法治疗的疾病。值得庆幸的是，对所有人的普遍护理有了很大改善，大约90%的儿童得到了治愈。不幸的是，ALL中仍有一些罕见的子集有复发的趋势，并且无法治疗。我们正试图了解这些罕见的、不可治愈的ALL的分子细节，以便设计新的治疗方法。为了做到这一点，我们研究了表观遗传学如何影响基因调控。基因是由DNA组成的，它们驻留在细胞核中，在那里它们充当细胞的硬件，需要被“读取”才能发挥作用。当基因被不适当地读取(或我们所说的“激活”)时，可能会导致癌症生长等异常行为。表观遗传学是不直接存储在DNA本身中的信息。例如，一些表观遗传信息存储在组蛋白携带的化学修饰中，组蛋白在一种名为染色质的结构中与DNA相互作用。越来越清楚的是，异常的表观遗传变化不仅在许多人类疾病中很常见，例如白血病，而且这些变化本质上是可逆的。我们的目标是帮助设计针对这些可逆表观遗传变化的疗法。

项目成果

Phenotypic screening identifies a trisubstituted imidazo[1,2-a]pyridine series that induces differentiation in multiple AML cell lines.

表型筛选鉴定出可诱导多种 AML 细胞系分化的三取代咪唑并[1,2-a]吡啶系列。

• DOI: 10.1016/j.ejmech.2023.115509
• 发表时间: 2023
• 期刊: European journal of medicinal chemistry
• 影响因子: 6.7
• 作者: Josa-Culleré L

MLL-AF4 cooperates with PAF1 and FACT to drive high-density enhancer interactions in leukemia.

• DOI: 10.1038/s41467-023-40981-9
• 发表时间: 2023-08-25
• 期刊: NATURE COMMUNICATIONS
• 影响因子: 16.6
• 作者: Crump, Nicholas T.;Smith, Alastair L.;Godfrey, Laura;Dopico-Fernandez, Ana M.;Denny, Nicholas;Harman, Joe R.;Hamley, Joseph C.;Jackson, Nicole E.;Chahrour, Catherine;Riva, Simone;Rice, Siobhan;Kim, Jaehoon;Basrur, Venkatesha;Fermin, Damian;Elenitoba-Johnson, Kojo;Roeder, Robert G.;Allis, C. David;Roberts, Irene;Roy, Anindita;Geng, Huimin;Davies, James O. J.;Milne, Thomas A.
• 通讯作者: Milne, Thomas A.

Disrupted propionate metabolism evokes transcriptional changes in the heart by increasing histone acetylation and propionylation

• DOI: 10.1038/s44161-023-00365-0
• 发表时间: 2023-12-01
• 期刊: NATURE CARDIOVASCULAR RESEARCH
• 作者: Park，Kyung Chan;Crump，Nicholas T.;Swietach，Pawel
• 通讯作者: Swietach，Pawel

Modelling acquired resistance to DOT1L inhibition exhibits the adaptive potential of KMT2A-rearranged acute lymphoblastic leukemia.

• DOI: 10.1186/s40164-023-00445-8
• 发表时间: 2023-09-22
• 期刊: EXPERIMENTAL HEMATOLOGY & ONCOLOGY
• 影响因子: 10.9
• 作者: Schneider, Pauline;Crump, Nicholas T.;Arentsen-Peters, Susan T. C. J. M.;Smith, Alastair L.;Hagelaar, Rico;Adriaanse, Fabienne R. S.;Bos, Romy S.;de Jong, Anja;Nierkens, Stefan;Koopmans, Bianca;Milne, Thomas A.;Pieters, Rob;Stam, Ronald W.
• 通讯作者: Stam, Ronald W.

Alkaline nucleoplasm facilitates contractile gene expression in the mammalian heart.

• DOI: 10.1007/s00395-022-00924-9
• 发表时间: 2022-03-31
• 期刊: Basic research in cardiology
• 影响因子: 9.5
• 作者: Hulikova A;Park KC;Loonat AA;Gunadasa-Rohling M;Curtis MK;Chung YJ;Wilson A;Carr CA;Trafford AW;Fournier M;Moshnikova A;Andreev OA;Reshetnyak YK;Riley PR;Smart N;Milne TA;Crump NT;Swietach P
• 通讯作者: Swietach P