Targeting the ARHGAP25 pathway in acute myelogenous leukemia stem cells

靶向急性髓性白血病干细胞中的 ARHGAP25 通路

• 批准号: 10177875
• 负责人: Leo D. Wang
• 金额: $ 16.96万
• 依托单位: BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-01 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10177875
• 关键词: Actins; Acute Myelocytic Leukemia; Address; Advisory Committees; Area; Award; Biochemical; Biochemistry; Boston; CXCL12 gene; CXCR4 gene; Cancer Biology; Cell Line; Cell Maintenance; Cell physiology; Cells; Chemoresistance; Child; Chimeric Proteins; Clinical; Combined Modality Therapy; Conceptions; Dana-Farber Cancer Institute; Data; Development; Development Plans; Diabetes Mellitus; Differentiation and Growth; Disease; Ensure; Environment; Event; Family; Funding; Future; GTPase-Activating Proteins; Genetic Transcription; Genomics; Goals; Grant; Growth and Development function; Guanosine Triphosphate; HOXA9 gene; Hematological Disease; Hematopoiesis; Hematopoietic; Hematopoietic stem cells; Human; Hydrolysis; Impairment; In Vitro; Institutes; International; Investigation; Kinetics; Laboratories; MLL-AF9; Maintenance; Malignant - descriptor; Malignant Neoplasms; Mass Spectrum Analysis; Measures; Mediating; Medicine; Mentors; Mentorship; Modeling; Monomeric GTP-Binding Proteins; Mus; Myelogenous; Myeloid Leukemia; Myelopoiesis; NUP98 gene; Nature; Oncogenes; Oncogenic; Oncology; Outcome; Pathway interactions; Pediatric Hematology; Pediatric Hospitals; Phosphorylation; Physicians; Population; Post-Translational Protein Processing; Protein Dephosphorylation; Proteins; Proto-Oncogene Proteins c-akt; Publications; RUNX1 gene; Relapse; Research; Research Personnel; Research Proposals; Research Training; Resistance; Role; Scientist; Serine; Signal Transduction; Stem Cell Development; Stem cell transplant; Structure; System; Techniques; Tertiary Protein Structure; Testing; Time; Training; Transplantation; United States National Institutes of Health; Universities; Wages; Work; acute myeloid leukemia cell; base; career; career development; cell transformation; combinatorial; design; differential expression; experience; experimental study; improved; in vivo; inhibitor/antagonist; insight; leukemia; leukemic stem cell; leukemic transformation; leukemogenesis; molecular targeted therapies; mutant; novel; novel therapeutics; phosphoproteomics; progenitor; programs; protein function; relapse patients; retroviral transduction; rho; stem; stem cell biology; stem cell survival; stem cell therapy; stem cells; tenure track

Project Summary/Abstract Research: Acute myeloid leukemia (AML) has a high relapse rate and is very difficult to cure, in large part due to the persistence of quiescent, chemotherapy-resistant leukemia stem cells (LSCs). Successful eradication of LSCs would greatly improve AML cure rates, but specific targeting of LSCs has been difficult to achieve because LSCs are rare and difficult to study. This proposal builds on my novel preliminary data indicating that the Rac-GAP Arhgap25 is required for leukemic transformation of HSCs. To understand more fully the requirement for and mechanisms underpinning the role of Arhgap25 AML leukemogenesis, I propose three distinct and complementary lines of investigation in this application, all of which target LSC survival and maintenance. First, I will fully characterize the cell-of-origin-specific nature of the requirement for Arhgap25 in leukemogenesis in multiple models of AML. Second, I will identify the phosphorylation events that permit or prohibit the ability of Arhgap25 to contribute to leukemogenesis. Finally, I will dissect the biochemical mechanisms responsible for Arhgap25 requirement in the maintenance and survival of AML LSCs. These studies will lay the groundwork for developing clinically useful combination therapies for AML and, ultimately, improving AML cure rates. Environment: The Dana-Farber Cancer Institute (DFCI), Boston Children’s Hospital (BCH), and the Joslin Diabetes Center at Harvard University are internationally recognized research programs with a number of world-renowned researchers in the areas of stem cell biology, hematopoiesis, and cancer biology. The Division of Pediatric Hematology/Oncology/Stem Cell Transplantation at the Dana-Farber/Boston Children’s Cancer and Blood Disorders Center, in particular, has a long and distinguished record of training successful physician-scientists. I have assembled an excellent mentoring and advisory committee, consisting of Dr. Amy Wagers, Dr. David Williams, Dr. Leonard Zon, Dr. Kimberly Stegmaier, and Dr. Yi Zheng, who will guide me through my research and training experiences. Dr. Zheng, who has joined my advisory committee for this resubmission, is one of the world’s experts in small GTPase biochemistry, and will aid significantly in providing essential additional training in Rac biochemical techniques and strategies. Candidate Career Goals: My long-term career objective is to compete successfully for R01 funding as a tenure-track, independent physician-scientist in a pediatric hematology/oncology/stem cell transplantation department. A K08 award will provide the senior mentorship and expertise needed to advance my training, develop my proficiency in new techniques, and develop my mastery of new concepts. It will also provide critically important protected time so that I can develop my ideas and projects and bring them to publication in support of further NIH grant submissions. This research proposal is part of a structured plan with scientific, technical, clinical, and career developmental components. The research will be performed under the guidance of Dr. Amy Wagers at the Joslin Diabetes Center and Harvard Stem Cell Institute and Dr. David Williams at the Boston Children’s Hospital and Dana-Farber Cancer Institute. The career development plan builds upon my prior research and clinical experiences with the goal of ensuring that I acquire the expertise required to become a successful, independent investigator with a focus on translational leukemia stem cell therapeutics.

项目概要/摘要 研究：急性髓系白血病（AML）复发率高，治愈难度大， 很大程度上是由于静止的、化疗耐药的白血病干细胞的持续存在 （LSC）的成功根除将大大提高 AML 的治愈率，但具体而言。 LSC 的靶向很难实现，因为 LSC 很少且难以研究。 该提案建立在我新颖的初步数据之上，表明需要 Rac-GAP Arhgap25 更全面地了解 HSC 的白血病转化的要求。 为了了解 Arhgap25 AML 白血病发生作用的机制，我提出了三种不同的机制 以及本申请中的补充研究路线，所有这些都以 LSC 存活和 首先，我将充分描述细胞来源特定性的要求。 Arhgap25 在多种 AML 模型中的白血病发生中的作用 其次，我将确定 Arhgap25 在多种 AML 模型中的作用。 允许或禁止 Arhgap25 参与的磷酸化事件 最后，我将剖析负责 Arhgap25 的生化机制。 这些研究将为 AML LSC 的维持和存活奠定基础。 为临床上有用的 AML 联合疗法开发基础，并最终 提高 AML 治愈率。 环境：丹纳法伯癌症研究所 (DFCI)、波士顿儿童医院 (BCH) 和 哈佛大学乔斯林糖尿病中心是国际公认的研究 与干细胞生物学领域的许多世界知名研究人员合作的项目， 造血和癌症生物学小儿血液学/肿瘤学/干细胞科。 丹纳法伯/波士顿儿童癌症和血液疾病中心的移植 特别是，在培养成功的医师科学家方面拥有悠久而杰出的记录。 组建了一个优秀的指导和咨询委员会，由 Amy Wagers 博士、Dr. David Williams、Leonard Zon 博士、Kimberly Stegmaier 博士和 Yi Cheng 博士将指导我 通过我的研究和培训经验，郑博士加入了我的顾问团队。 此次重新提交的委员会是世界上小 GTP 酶生物化学领域的专家之一， 并将有助于在 Rac 生化技术方面提供重要的额外培训 和策略。 候选人职业目标：我的长期职业目标是成功竞争 R01 作为儿科领域的终身教授、独立医师科学家获得资助 血液学/肿瘤学/干细胞移植部门将授予高级人员K08奖。 推进我的培训、提高我在新领域的熟练程度所需的指导和专业知识 技术，并培养我对新概念的掌握，这也将提供至关重要的信息。 受保护的时间，以便我可以发展我的想法和项目，并将它们发表在 支持进一步提交 NIH 拨款。该研究提案是结构化计划的一部分。 该研究将包含科学、技术、临床和职业发展组成部分。 在 Joslin 糖尿病中心和哈佛大学的 Amy Wagers 博士的指导下进行 干细胞研究所和波士顿儿童医院的 David Williams 博士以及丹娜—法伯癌症研究所 癌症研究所的职业发展计划建立在我之前的研究和临床基础上。 经验的目标是确保我获得成为一名 成功的独立研究者，专注于转化白血病干细胞 疗法。

项目成果

Tumor inflammation-associated neurotoxicity.

• DOI: 10.1038/s41591-023-02276-w
• 发表时间: 2023-04
• 期刊: Nature medicine
• 影响因子: 82.9
• 作者: Mahdi J;Dietrich J;Straathof K;Roddie C;Scott BJ;Davidson TB;Prolo LM;Batchelor TT;Campen CJ;Davis KL;Gust J;Lim M;Majzner RG;Park JR;Partap S;Ramakrishna S;Richards R;Schultz L;Vitanza NA;Wang LD;Mackall CL;Monje M
• 通讯作者: Monje M

Vitamin C, From Supplement to Treatment: A Re-Emerging Adjunct for Cancer Immunotherapy?

• DOI: 10.3389/fimmu.2021.765906
• 发表时间: 2021
• 期刊: Frontiers in immunology
• 影响因子: 7.3
• 作者: Kouakanou L;Peters C;Brown CE;Kabelitz D;Wang LD
• 通讯作者: Wang LD

ALL the comforts of homing: lymphoblasts find cerebrospinal fluid inhospitable without meningeal cell contact.

归巢的所有舒适：淋巴母细胞在没有脑膜细胞接触的情况下发现脑脊液不适宜居住。

• DOI: 10.1111/bjh.16368
• 发表时间: 2020
• 期刊: British journal of haematology
• 影响因子: 6.5
• 作者: Manousopoulou,Antigoni;Wang,LeoD
• 通讯作者: Wang,LeoD