Analysis of the leukemic stem cell niche in chronic myeloid leukemia

慢性粒细胞白血病白血病干细胞生态位分析

• 批准号: 7787671
• 负责人: Daniela Sandra Krause
• 金额: $ 15.64万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7787671
• 关键词: AMD3100; Acute leukemia; Advisory Committees; Affect; Animal Model; Area; B-Cell Acute Lymphoblastic Leukemia; Basic Science; Biological Assay; Biology; Blast Phase; Blood Banks; Blood Transfusion; Bone Marrow; Boston; CD44 gene; Cancer Biology; Cancer Center; Cell Communication; Cells; Chronic Myeloid Leukemia; Clinical; Clinical Pathology; Coagulation Process; Cytostatics; Data; Development; Disease; Education; Educational process of instructing; Engraftment; Environment; Ethics; Fellowship; Floor; Future; General Hospitals; Goals; Granulocyte Colony-Stimulating Factor; Healthcare; Hematology; Hematopoietic stem cells; High Prevalence; Home environment; Homing; Hybrids; Imatinib; In Vitro; Institutes; Institution; Interferons; Laboratories; Lead; Leukemic Cell; Location; Massachusetts; Medical; Medical center; Medicine; Mentored Clinical Scientist Development Award (K08); Mentors; Microanatomy; Microarray Analysis; Microscopy; Modeling; Modification; Morphology; Mus; Mutate; Mutation; Myeloproliferative disease; Oncogenes; Osteoblasts; Outcome; Parathyroid Hormone Receptor; Parathyroid Hormone Receptors; Pharmaceutical Preparations; Pharmacological Treatment; Phase; Phenotype; Physicians; Population; Publishing; Regenerative Medicine; Research; Research Personnel; Research Training; Resistance; Resources; Role; Science; Scientist; Services; Stem cells; Technology; Testing; Time; Training; Training Activity; Transfusion; Transplant Recipients; Transplantation; Tyrosine Kinase Inhibitor; Work; base; bcr-abl Fusion Proteins; bone; bone cell; cancer genetics; career; fusion gene; improved; in vivo; lectures; leukemia; malignant phenotype; medical schools; meetings; member; mouse model; mutant; novel; novel strategies; oncology; professor; progenitor; programs; promoter; protein expression; public health relevance; research study; responsible research conduct; spatial relationship; statistics; stem cell biology; stem cell niche; treatment strategy; two-photon

DESCRIPTION (provided by applicant): I am currently a research fellow in Dr. David Scadden's laboratory at The Center for Regenerative Medicine and Massachusetts General Hospital (MGH). I have completed the clinical requirements of my fellowship in transfusion medicine in the Harvard-wide program. My education as a physician scientist has focused on developing clinical expertise in hematology/oncology and clinical pathology/ transfusion medicine and basic research training on the study of leukemia. I am applying for a Mentored Clinical Scientist Development Award (K08) in order to have protected time to acquire additional scientific training in stem cell biology and in-vivo microscopy and to prepare for a career as an independent researcher. My long-term career goal is to establish a career as an independent physician scientist at a major academic institution dedicating at least 75% of my time to basic research and 25% of my time to clinical work and teaching in a blood transfusion and/or coagulation service. The Scadden Laboratory is an ideal choice for my training and eventual path to scientific independence, as Dr. Scadden, who is an excellent mentor, is known worldwide for his work in hematopoietic stem cell biology and the bone marrow microenvironmental niche. He has an excellent track record of training young scientists. The Center of Regenerative Medicine is a very collaborative environment providing me with immediate access to well-known and well-established research investigators who are applying cutting-edge technologies and model organisms highly relevant to many different areas of biology, including stem cell and cancer biology and cancer genetics. In addition I can make use of all the resources available to me at The MGH Center for Regenerative Medicine, Harvard Medical School, Massachusetts General Hospital, The Harvard Stem Cell Institute and within the Scadden Laboratory. I am very fortunate to have an advisory committee consisting of Dr. Scadden, Dr. Van Etten, Chief of Hematology/Oncology at Tufts Medical Center and a leading expert in CML and other myeloproliferative disorders, and Dr. Charles Lin, Associate Professor at the Wellman Center for Photomedicine. I will formally and regularly meet with my mentor and my advisors individually and in four- way meetings. I will also be able to benefit greatly from my advisors' contacts to other scientists in their respective fields As part of my scientific training I will pursue formal graduate level coursework in ethics, statistics and stem cell biology through the Harvard Medical School Division of Medical Sciences. In addition, I will attend the weekly lab meetings of our laboratory, floor meetings with members of the Center for Regenerative Medicine and the Cancer Center, seminars at the Center for Regenerative Medicine and the other academic institutions in Boston. I plan to attend two scientific meetings per year. I received training in the responsible conduct of research through the Partners Healthcare Program in the Responsible Conduct of Research. I will continue to teach 4 lectures to blood bank/coagulation residents at MGH and I plan to do a limited amount of clinical work by signing out coagulation cases at MGH and attending in the MGH blood bank. I have chosen to focus my research on analyzing the LSC niche in chronic myeloid leukemia (CML), as understanding of the biology of the LSC niche and, ultimately, the development of strategies to manipulate this niche will improve current and future treatment strategies for leukemia. This is important, as tyrosine kinase inhibitors (TKIs) have limited efficacy targeting leukemic stem cells (LSCs) despite now being the treatment of choice for CML. It is believed that the LSC niche provides a "sanctuary" for LSC where they are protected from the cytostatic effects of therapy. Lack of eradication of the LSC can lead to progression of CML to the blastic phase which closely resembles an acute leukemia. Targeting the LSC and LSC-niche interactions, therefore, is an important and novel goal in the treatment of CML and builds on my prior work in Dr. Van Etten's laboratory, where we first defined the interactions of the LSC with its bone marrow microenvironment. Preliminary functional experiments in the murine transduction/transplantation model of CML and B-cell acute lymphoblastic leukemia (B-ALL) in Dr. Scadden's laboratory demonstrate that niche modification can affect leukemic outcome. Furthermore, interaction of CML cells with their niche alters niche components like osteoblasts. The goals of my proposal therefore are: * To determine the microanatomy of the BM (BM) microenvironment in CML. * To test how leukemic cells and osteoblasts mutually interact with each other. * To test whether pharmacological treatment can alter the microanatomy of the leukemic stem cell niche and alter the malignant phenotype. In summary, the proposed research and training activities constitute a comprehensive program which will allow me to grow as a scientist and transition to a career as an independent researcher. Simultaneously, I hope to discover ways to influence the malignant phenotype of the leukemia and means to target the LSC in its niche, in order to, ultimately, add to the improvement of therapy for this intractable disease. PUBLIC HEALTH RELEVANCE: A cure of chronic myeloid leukemia (CML), one of the leukemias with the highest prevalence, is impeded by the resistance of the leukemic stem cell to imatinib, the drug of choice for this disease. It is hypothesized that the leukemic stem cells reside in a "sanctuary" within the bone marrow, where the leukemic cells are produced. The goals of this project are to define the microanatomy of this niche by use of in-vivo microscopy and a mouse model of CML, to manipulate the bone cells, the osteoblasts, which are constituents of this niche and to define strategies by which to dislocate the leukemic stem cells from their "sanctuary", in order to render them more sensitive to therapy with imatinib.

描述（由申请人提供）：我目前是再生医学中心和麻省总医院 (MGH) David Scadden 博士实验室的研究员。我已经完成了哈佛大学输血医学项目的临床要求。作为一名医师科学家，我的教育重点是发展血液学/肿瘤学和临床病理学/输血医学的临床专业知识以及白血病研究的基础研究培训。我正在申请指导临床科学家发展奖 (K08)，以便有足够的时间获得干细胞生物学和体内显微镜方面的额外科学培训，并为独立研究员的职业生涯做好准备。我的长期职业目标是在一家主要学术机构建立独立医师科学家的职业生涯，将至少 75% 的时间用于基础研究，25% 的时间用于临床工作和输血和/或教学凝血服务。 Scadden 实验室是我接受培训和最终走向科学独立的理想选择，因为 Scadden 博士是一位优秀的导师，因其在造血干细胞生物学和骨髓微环境领域的工作而闻名于世。他在培养年轻科学家方面有着出色的记录。再生医学中心是一个高度协作的环境，使我能够立即接触到知名且成熟的研究人员，他们正在应用与许多不同生物学领域（包括干细胞和癌症生物学）高度相关的尖端技术和模型生物体和癌症遗传学。此外，我还可以利用麻省总医院再生医学中心、哈佛医学院、马萨诸塞州总医院、哈佛干细胞研究所和斯卡登实验室内的所有可用资源。我很幸运有一个顾问委员会，成员包括 Scadden 博士、塔夫茨医学中心血液学/肿瘤科主任、CML 和其他骨髓增殖性疾病领域的领先专家 Van Etten 博士，以及塔夫茨医学中心副教授 Charles Lin 博士。韦尔曼光医学中心。我将定期与我的导师和顾问进行正式和定期的单独会面以及四方会议。我还将能够从我的顾问与各自领域的其他科学家的接触中受益匪浅 作为我科学培训的一部分，我将通过哈佛医学院医学科学部攻读伦理学、统计学和干细胞生物学方面的正式研究生课程。此外，我还将参加我们实验室的每周实验室会议、与再生医学中心和癌症中心成员的现场会议、再生医学中心和波士顿其他学术机构的研讨会。我计划每年参加两次科学会议。我通过负责任的研究行为合作伙伴医疗保健计划接受了负责任的研究行为培训。 我将继续为 MGH 的血库/凝血住院医师讲授 4 场讲座，并计划通过在 MGH 签出凝血病例并到 MGH 血库就诊来完成有限的临床工作。 我选择将研究重点放在分析慢性粒细胞白血病 (CML) 中的 LSC 生态位，因为了解 LSC 生态位的生物学以及最终开发操纵该生态位的策略将改善当前和未来的白血病治疗策略。这一点很重要，因为酪氨酸激酶抑制剂 (TKI) 尽管目前是 CML 的首选治疗方法，但针对白血病干细胞 (LSC) 的疗效有限。据信，LSC 生态位为 LSC 提供了一个“避难所”，在那里它们受到保护，免受治疗的细胞抑制作用。如果不根除 LSC，可能会导致 CML 进展至急变期，这与急性白血病非常相似。因此，针对 LSC 和 LSC 生态位相互作用是治疗 CML 的一个重要且新颖的目标，它建立在我之前在 Van Etten 博士实验室的工作基础上，在那里我们首先定义了 LSC 与其骨髓微环境的相互作用。 Scadden 博士实验室在 CML 和 B 细胞急性淋巴细胞白血病 (B-ALL) 小鼠转导/移植模型中进行的初步功能实验表明，生态位修饰可以影响白血病结果。此外，CML 细胞与其生态位的相互作用会改变成骨细胞等生态位成分。因此，我的提案的目标是： * 确定 CML 中 BM (BM) 微环境的微观解剖结构。 * 测试白血病细胞和成骨细胞如何相互作用。 * 测试药物治疗是否可以改变白血病干细胞生态位的微观解剖结构并改变恶性表型。 总之，拟议的研究和培训活动构成了一个全面的计划，使我能够成长为一名科学家，并过渡到作为一名独立研究员的职业生涯。同时，我希望找到影响白血病恶性表型的方法以及针对LSC的利基的方法，以便最终改善这种难治性疾病的治疗。 公共卫生相关性：慢性粒细胞白血病 (CML) 是发病率最高的白血病之一，其治愈因白血病干细胞对伊马替尼（治疗该疾病的首选药物）的耐药性而受到阻碍。据推测，白血病干细胞存在于骨髓内的“避难所”，白血病细胞就是在那里产生的。该项目的目标是通过使用体内显微镜和 CML 小鼠模型来定义该生态位的显微解剖结构，以操纵作为该生态位组成部分的骨细胞、成骨细胞，并定义使该生态位脱位的策略将白血病干细胞从其“避难所”中取出，以使它们对伊马替尼治疗更加敏感。