Dissecting the Functional Role of Monocytes in B-cell Acute Lymphoblastic Leukemia Survival

剖析单核细胞在 B 细胞急性淋巴细胞白血病生存中的功能作用

• 批准号: 10621136
• 负责人: Matthew Witkowski
• 金额: $ 18.45万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-12 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10621136
• 关键词: 3-Dimensional; Ablation; Acute leukemia; Adult Precursor B Lymphoblastic Leukemia; Animal Model; Award; B-Cell Acute Lymphoblastic Leukemia; B-Lymphocyte Subsets; B-cell precursor acute lymphoblastic leukemia cell; Behavior; Bioinformatics; Biological; Biological Markers; Biology; Blood Vessels; Bone Marrow; CD14 gene; Cells; Chemoprotective Agent; Childhood; Childhood Leukemia; Childhood Precursor B Lymphoblastic Leukemia; Clinical; Clinical Trials; Collaborations; Combined Modality Therapy; Data; Development; Development Plans; Devices; Diagnosis; Disease; Disease Progression; Disease Resistance; Disease remission; Emergency Situation; Endothelium; Epigenetic Process; Experimental Leukemia; FCGR3B gene; Failure; Fostering; Foundations; Genetic; Goals; Human; Image; Immune; Immunology; Immunotherapeutic agent; Immunotherapy; Knowledge; Laboratories; Leukemia Acute Lymphoblastic Chemotherapy; Macrophage Colony-Stimulating Factor; Macrophage Colony-Stimulating Factor Receptor; Maintenance; Manuscripts; Maps; Microfluidics; Modeling; Mus; Myelogenous; Myeloid Cells; Patient-Focused Outcomes; Patients; Pediatric Hospitals; Play; Population; Postdoctoral Fellow; Preparation; Receptor Inhibition; Relapse; Remission Induction Therapy; Reporter; Research; Research Personnel; Resistance; Resolution; Role; Sampling; Specimen; Suggestion; Testing; Texas; Therapeutic; Training; Transition Career Development Award (K22); Treatment Protocols; Treatment outcome; United States National Institutes of Health; Universities; Vascular Endothelial Cell; Vascular Endothelium; Vascularization; Visualization; Work; Xenograft procedure; behavioral study; cancer therapy; career development; chemotherapy; cohort; early phase clinical trial; effectiveness evaluation; experience; first responder; improved; in vivo; inhibitor; leukemia; leukemia treatment; monocyte; mouse model; neoplastic cell; patient response; pre-clinical; programs; public health relevance; repaired; research and development; response; therapy resistant; treatment response; tumor; tumor-immune system interactions; two photon microscopy; two-photon

Scientific Abstract The bone marrow microenvironment most likely plays a significant role in promoting B-cell acute lymphoblastic leukemia (B-ALL) survival, progression, and escape from treatment. Our preliminary studies utilized single-cell profiling approaches to comprehensively map the primary human B-ALL bone marrow immune microenvironment throughout three distinct stages of the disease: diagnosis, remission and relapse. Importantly, we uncovered a role for leukemia-associated monocyte subpopulations in B-ALL survival, demonstrating that monocyte abundance at diagnosis is predictive of pediatric and adult B-ALL patient outcomes. Using a three-dimensional (3D) microfluidics-based organotypic device, we show that human B-ALL blasts alter a vascularized microenvironment to promote monocytic differentiation and depletion of leukemia associated myeloid cells in Ph+ B-ALL animal models leads to prolonged disease remission in vivo. This project will determine the precise origins and function of nonclassical monocytes in supporting B-ALL survival and, ultimately, target leukemia-supporting monocytes to enhance the efficacy of existing ALL therapy. To achieve this, we will use two-photon live-imaging to assess nonclassical monocytes' behavior within the leukemic niche. We will then take advantage of murine strains lacking nonclassical monocytes, as well as established single-cell profiling approaches, to assess monocyte abundance's impact on the remodeling of a vascularized leukemic niche in vivo. We will expand our flow cytometric analysis of large cohorts of primary pediatric B-ALL patient samples to establish the association between monocyte abundance, monocyte differentiation state, and patient treatment outcome through a collaboration with pediatric leukemia experts, Drs. Karen Rabin (Baylor University/Texas Children's Hospital) and Charles Mullighan (St Jude Children's Hospital). Finally, murine and human xenograft pre-clinical in vivo B-ALL platforms to determine the impact of depleting leukemia-supporting monocytes (anti-CSF1R therapy) in combination with conventional B-ALL chemotherapy on B-ALL survival. These findings will ultimately provide the basis for clinical trials combining CSF1R inhibition with existing B-ALL therapeutics. This proposal outlines my career development plan for obtaining the necessary preparation to transition into a successful independent investigator. My postdoctoral supervisor, Dr. Iannis Aifantis, fully supports my distinct research program. My ongoing training with experts in nonclassical monocyte biology (Dr. Hedricks, La Jolla Institute for Immunology), live in vivo two-photon microscopy (David Fooksman, Albert Einstein) and single-cell bioinformatics (Dr. Tsirigos, NYU Applied Bioinformatics Laboratories) will provide the essential knowledge to accomplish my long-term scientific goals. Collectively, the proposed research and career development plans will generate data with a significant impact on immune-based therapies in pediatric leukemia and provide the basis of my future research as an independent researcher.

科学抽象 骨髓微环境很可能在促进B细胞急性淋巴细胞性白血病中起重要作用。 白血病（B-ALL）生存、进展和逃避治疗。我们的初步研究利用单细胞 用于全面绘制原发性人B-ALL骨髓免疫图的分析方法 在疾病的三个不同阶段：诊断，缓解和复发。 重要的是，我们发现白血病相关单核细胞亚群在B-ALL生存中的作用， 证明诊断时单核细胞丰度可预测儿童和成人B-ALL患者 成果。使用三维（3D）微流体为基础的器官型装置，我们表明，人类B-ALL 原始细胞改变血管化微环境以促进单核细胞分化和白血病耗竭 Ph+ B-ALL动物模型中的相关骨髓细胞导致体内疾病缓解延长。这个项目 将确定非经典单核细胞在支持B-ALL存活中的确切来源和功能， 最终，靶向支持白血病的单核细胞，以增强现有ALL疗法的疗效。实现 为此，我们将使用双光子实时成像来评估白血病细胞内非经典单核细胞的行为。 利基然后，我们将利用缺乏非经典单核细胞的小鼠品系，以及建立的 单细胞分析方法，以评估单核细胞丰度对血管化的 体内白血病小生境我们将扩大我们的流式细胞术分析的大队列原发性儿科B-ALL 患者样本，以建立单核细胞丰度、单核细胞分化状态和单核细胞增殖之间的关联。 通过与儿科白血病专家Karen Rabin博士（贝勒医学院）的合作， 大学/得克萨斯州儿童医院）和查尔斯Mullighan（圣裘德儿童医院）。最后，小鼠和 人异种移植临床前体内B-ALL平台，以确定消耗白血病支持性 单核细胞（抗CSF 1 R治疗）联合常规B-ALL化疗对B-ALL生存期的影响。 这些发现最终将为CSF 1 R抑制与现有B-ALL联合的临床试验提供基础 治疗学这份建议书概述了我的职业发展计划，以获得必要的准备， 成为一名成功的独立调查员。我的博士后导师，Iannis Aifantis博士， 支持我独特的研究项目我正在进行的培训与专家在非经典单核细胞生物学（博士。 Hedricks，拉霍亚免疫学研究所），活体内双光子显微术（大卫福克斯曼，阿尔伯特 爱因斯坦）和单细胞生物信息学（Tsirigos博士，纽约大学应用生物信息学实验室）将提供 实现我的长期科学目标所必需的知识。总体而言，拟议的研究和 职业发展计划将产生对儿科免疫治疗有重大影响的数据 白血病，并为我未来作为一名独立研究人员的研究提供基础。