The role of epigenetic plasticity in acute myeloid leukemia cell persistence

项目摘要 急性髓性白血病（AML）患者的预后不佳，主要是因为目前的治疗方法无法 根除所有AML细胞，留下持续存在的癌细胞，导致复发。AML细胞的生存能力 治疗与干细胞特性相关1，2。这些原始的AML细胞需要被根除， 持久缓解。在我读博士的时候。在约翰·迪克博士的培训下，我研究了造血干细胞1，3， 启发我专攻AML中干细胞状态的表观遗传调控。为了我的博士后训练，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， 稀有细胞中的组蛋白修饰4.利用这项技术，我以前所未有的精确度描述了干细胞 基因被组蛋白3赖氨酸27三甲基化（H3 K27 me 3）沉默，这是一种抑制性表观遗传修饰， 由PRC 2催化并由KDM 6拮抗。PRC 2在AML中经常受损，导致增强的 干细胞的特性，但H3 K27脱甲基酶KDM 6的作用是未知的。我发现KDM 6可以促进 AML细胞适应性，并且在具有IDH 1/2（IDHmut）突变的AML细胞中上调，表明IDH 1/2的依赖性。 IDHmut AML细胞对KDM 6功能的影响。本研究的目的是：（1）研究KDM 6的功能 使用各种人AML细胞模型，（2）评估KDM 6作为IDHmut AML细胞中的治疗靶标，和（3） 描述KDM 6通过识别其下游靶点促进AML细胞适应性的机制。这些 研究将揭示一种新的驱动AML的表观遗传机制，并为AML的发展奠定基础。 KDM 6抑制剂，以促进有效根除AML细胞，包括那些持续通过电流 治疗 伯恩斯坦博士是一位杰出的导师，他的学员在以下领域获得了组长职位： 学术界他是表观基因组学、癌症和发展领域的国际知名领导者， 在马萨诸塞州总医院（MGH）、哈佛医学院、美国癌症协会的预约 和布罗德研究所该研究将在MGH进行，MGH是一家着名的研究机构和医疗机构。 该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， 布里格姆妇女医院和布罗德研究所，一个促进合作的环境， 智力交流。一个由世界级的医生和科学家组成的研究咨询委员会将提供建议 大卫斯卡登博士、乔恩·阿斯特博士和安德鲁·莱恩博士。研究的关键方面将是 通过与安德鲁·莱恩、大卫·温斯托克和查尔斯·爱泼斯坦博士的合作完成。 K99/R 00奖项将为我提供实现职业目标的最佳机会。的详细 培训计划包括一个研究咨询委员会和发展领导和指导技能， 将是成功过渡到独立的宝贵因素。R 00阶段的奖励将允许我 在一家顶级癌症研究所获得独立职位，并建立一个雄心勃勃的研究计划。 1. P.货车Galen等人，自然510，268-272（2014）。 2. P.货车Galen等人，正在接受《科学》杂志的审查（见附录）。 3. P.货车Galen等人，干细胞移植14，94-106（2014）。 4. P.货车Galen等人，摩尔Cell. 61，170-180（2016）。

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).