The role of epigenetic plasticity in acute myeloid leukemia cell persistence

表观遗传可塑性在急性髓系白血病细胞持续存在中的作用

• 批准号: 10221637
• 负责人: Peter van Galen
• 金额: $ 24.9万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-01 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10221637
• 关键词: Academia; Acute Myelocytic Leukemia; Advisory Committees; American Cancer Society; Appointment; Award; Cancer Patient; Cell Line; Cell model; Cells; Chromatin; Collaborations; Communities; Complex; Dana-Farber Cancer Institute; Data; Dependence; Development; Disease remission; Doctor of Philosophy; Drug Targeting; Elements; Environment; Enzymes; Epigenetic Process; Excision; Fostering; Foundations; Gene Expression; Gene Silencing; General Hospitals; Genes; Genetic; Genetic Transcription; Genus Mentha; Goals; Hematopoietic; Histones; Homeobox Genes; Hospitals; Human; Impairment; In Vitro; Institutes; International; Knock-out; Laboratories; Lead; Lysine; Malignant Neoplasms; Maps; Massachusetts; Mediating; Medical center; Mentors; Metabolic; Modification; Molecular; Mutation; Nature; Outcome; Pathway interactions; Patient-Focused Outcomes; Patients; Pharmacology; Phase; Physicians; Polycomb; Positioning Attribute; Program Sustainability; Property; Recording of previous events; Recurrent disease; Relapse; Research; Research Institute; Research Proposals; Role; Sampling; Science; Scientist; Secure; Survival Rate; Technology; Testing; Training; Treatment Efficacy; Woman; acute myeloid leukemia cell; attenuation; base; biological adaptation to stress; cancer cell; career; chemotherapy; demethylation; epigenetic regulation; epigenomics; fitness; histone demethylase; histone modification; improved; in vivo; inhibitor/antagonist; innovative technologies; leadership development; leukemia; medical schools; mutant; novel; novel strategies; novel therapeutic intervention; overexpression; post-doctoral training; programs; relapse patients; skills; stem; stem cell function; stem cell genes; stem cells; stemness; targeted treatment; therapeutic target

PROJECT SUMMARY Acute myeloid leukemia (AML) patients have poor outcomes, largely because current therapies fail to eradicate all AML cells, leaving persistent cancer cells that drive relapse. The ability of AML cells to survive therapy is associated with stem cell properties1,2. These primitive AML cells need to be eradicated to achieve durable remissions. During my Ph.D. training with Dr. John Dick, I studied hematopoietic stem cells1,3 which inspired me to specialize in epigenetic regulation of the stem cell state in AML. For my postdoctoral training, I joined the laboratory of Dr. Bernstein, an expert in epigenetics, and developed an innovative technology to map histone modifications in rare cells4. Using this technology, I describe with unprecedented precision how stem cell genes are silenced by histone 3 lysine 27 trimethylation (H3K27me3), a repressive epigenetic modification that is catalyzed by PRC2 and antagonized by KDM6. PRC2 is frequently impaired in AML, leading to enhanced stem cell properties, but the role of the H3K27 demethylase KDM6 is unknown. I discovered that KDM6 promotes AML cell fitness and is upregulated in AML cells with mutations in IDH1/2 (IDHmut), indicating a dependency of IDHmut AML cells on KDM6 function. The objectives of this proposal are to (1) investigate the function of KDM6 using various human AML cell models, (2) evaluate KDM6 as a therapeutic target in IDHmut AML cells, and (3) delineate the mechanism by which KDM6 promotes AML cell fitness by identifying its downstream targets. These studies will uncover a novel epigenetic mechanism that drives AML and lay the foundation for the development of KDM6 inhibitors to facilitate efficient eradication of AML cells, including those that persist through current therapies. Dr. Bernstein is an outstanding mentor with a history of trainees that obtained group leader positions in academia. He is an internationally respected leader in the fields of epigenomics, cancer and development with appointments at the Massachusetts General Hospital (MGH), Harvard Medical School, American Cancer Society and the Broad Institute. The research will be carried out at MGH, a prestigious research institute and medical center that is part of a vibrant community that includes Harvard Medical School, Dana-Farber Cancer Institute, Brigham and Women's Hospital and the Broad Institute, an environment that fosters collaborations and intellectual exchange. A Research Advisory Committee of world-class physician-scientists will provide advice and guidance: Drs. David Scadden, Jon Aster and Andrew Lane. Critical aspects of the research will be completed through collaborations with Drs. Andrew Lane, David Weinstock and Charles Epstein. The K99/R00 award will provide me with the best opportunity to succeed in my career goals. The detailed training plan includes a Research Advisory Committee and development of leadership and mentoring skills that will be invaluable for a successful transition to independence. The R00 phase of the award will allow me to secure an independent position at a top cancer institute and set up an ambitious research program. 1. P. van Galen et al., Nature. 510, 268–272 (2014). 2. P. van Galen et al., under review at Science (see appendix). 3. P. van Galen et al., Cell Stem Cell. 14, 94–106 (2014). 4. P. van Galen et al., Mol. Cell. 61, 170–180 (2016).

项目摘要 急性髓样白血病（AML）患者的预后差，主要是因为当前疗法无法 根除所有AML细胞，留下驱动继电器的持续性癌细胞。 AML细胞生存的能力 治疗与干细胞特性有关1,2。这些原始的AML细胞需要放射性才能实现 持久的恢复。在我的博士学位期间与约翰·迪克（John Dick）博士进行培训，我研究了造血干细胞1,3 启发我专门研究AML中干细胞状态的表观遗传调节。对于我的博士后培训，我 加入了表观遗传学专家伯恩斯坦博士的实验室，并开发了一种创新技术来绘制 稀有细胞中的Hisstone修饰4。使用这项技术，我以前所未有的精度描述干细胞 组蛋白3赖氨酸27三甲基化（H3K27ME3）沉默，这是一种反射性表观遗传修饰，是 由PRC2催化并用KDM6拮抗。 PRC2经常在AML中受损，导致增强 干细胞特性，但是H3K27脱甲基酶KDM6的作用尚不清楚。我发现KDM6促进了 AML细胞适应性，并在IDH1/2（IDHMUT）突变的AML细胞中进行更新，表明 KDM6功能上的IDHMUT AML单元。该提案的目标是（1）研究KDM6的功能 使用各种人类AML细胞模型，（2）将KDM6评估为IDHMUT AML细胞中的治疗靶标，（3） 描述KDM6通过识别其下游靶标促进AML细胞适应性的机制。这些 研究将发现一种新型的表观遗传机制，该机制驱动AML并为发展奠定了基础 KDM6抑制剂的促进AML细胞的有效辐射，包括那些持续通过电流的细胞的抑制剂 疗法。 伯恩斯坦博士是一位出色的心理，拥有培训历史，在 学术界。他是表观基因组学，癌症和发展领域的国际尊敬的领导者 美国癌症协会哈佛医学院马萨诸塞州综合医院（MGH）的任命 和广泛的研究所。该研究将在著名的研究所和医学的MGH进行 中心是一个充满活力的社区的一部分，包括哈佛医学院，达纳 - 法伯癌症研究所， Brigham and妇女医院和Broad Institute，一个促进合作的环境 智力交流。世界一流的身体科学家研究咨询委员会将提供建议 和指导：Drs。大卫·斯卡德登（David Scadden），乔恩·阿斯特（Jon Aster）和安德鲁·莱恩（Andrew Lane）。研究的关键方面将是 通过与DRS的合作完成。安德鲁·莱恩（Andrew Lane），大卫·温斯托克（David Weinstock）和查尔斯·爱泼斯坦（Charles Epstein）。 K99/R00奖将为我提供成功实现职业目标的最佳机会。详细 培训计划包括一个研究咨询委员会以及发展领导力和心理技能的发展 成功过渡到独立将是无价的。奖励的R00阶段将使我能够 在顶级癌症研究所获得独立职位，并建立雄心勃勃的研究计划。 1。P.van Galen等人，自然。 510，268–272（2014）。 2。P.van Galen等人，在科学审查中（请参阅附录）。 3。P.van Galen等，细胞干细胞。 14，94–106（2014）。 4。P.van Galen等人，摩尔。细胞。 61，170–180（2016）。

项目成果

Single-Cell RNA Sequencing to Disentangle the Blood System.

• DOI: 10.1161/atvbaha.120.314654
• 发表时间: 2021-03
• 期刊: Arteriosclerosis, thrombosis, and vascular biology
• 作者: Acosta J;Ssozi D;van Galen P
• 通讯作者: van Galen P