Understanding and targeting bone marrow microenvironment in myelofibrosis

了解和靶向骨髓纤维化中的骨髓微环境

• 批准号: 10543555
• 负责人: Lei Ding
• 金额: $ 57.51万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-01-01 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10543555
• 关键词: Acute Myelocytic Leukemia; Adult; Allogenic; Apoptotic; Bone Marrow; Bone Marrow Cells; Cell Communication; Cell Cycle; Cell Death; Cells; Clinic; Collagen Fiber; Constitutional Symptom; Data; Deposition; Development; Disease; Disease remission; Fatty acid glycerol esters; Fibrosis; Fostering; Frequencies; Genetic; Hematopoiesis; Hematopoietic; Hematopoietic Stem Cell Transplantation; Hematopoietic stem cells; JAK2 gene; Knowledge; Leukemic Cell; Liver; Lung; Mediating; Mediator; Modeling; Molecular; Monoclonal Antibodies; Mus; Mutation; Myelofibrosis; Myeloproliferative disease; Myofibroblast; Neoplasms; Pathogenesis; Pathway interactions; Patients; Platelet-Derived Growth Factor alpha Receptor; Primary Myelofibrosis; Recurrence; Regulation; Reporting; Research; Reticulin; Retroviridae; Role; SPI1 gene; Skin; Source; Stem cell transplant; Stromal Cells; Testing; Therapeutic; Transplantation; Tyrosine Kinase Inhibitor; bone; cost; curative treatments; cytokine; design; effective therapy; efficacy testing; experimental study; in vivo; inhibitor; leptin receptor; leukemia; leukemic stem cell; mouse genetics; mutant; new therapeutic target; novel; novel therapeutics; prevent; self-renewal; side effect; synergism; targeted treatment; transcription factor; tumor microenvironment

Project summary/Abstract Understanding and targeting abnormal tumor microenvironment is critically important for developing effective therapy. Primary myelofibrosis (PMF) is a form of myeloproliferavtie neoplasm (MPN) that often progresses to lethal leukemia. Treatment options are limited for PMF, and the only potential cure, stem cell transplantation, is prohibitively toxic for most patients. Thus, novel and effective therapies are in great need for PMF. Recurrent mutations resulting in abnormal activation of the JAK-STAT pathway have been shown to be the driver of the disease. As a result, JAK inhibitors have been developed to treat PMF. However, these inhibitors only reduce some constitutional symptoms without significant impact on disease-causing leukemia stem cells (LSCs). A deeper understanding of the pathogenesis of PMF will offer the opportunity to better treat the disease. The bone marrow niche is a critical component to the pathogenesis of PMF. Our preliminary data show that bone marrow LepR+ stromal cells are the source of fibrosis. We have also identified several key mediators of LepR+ cell fibrosis. In this proposal, we propose to elucidating the cellular and molecular mechanisms of how LSCs interact with the fibrotic niche in vivo. We will test whether targeting the fibrosis mediators will lead to efficient elimination of LSCs and have synergistic effects with JAK inhibitors. By having a deeper understanding of the interaction between LSCs and the niche, our strategy of targeting the diseased niche may provide novel therapeutics to PMF.

项目概要/摘要 了解和靶向异常肿瘤微环境对于开发有效的 疗法原发性骨髓纤维化（PMF）是骨髓增生性肿瘤（MPN）的一种形式，通常进展为 致命的白血病PMF的治疗选择是有限的，唯一潜在的治愈方法是干细胞移植， 对大多数病人来说是有毒的。因此，非常需要新的和有效的治疗PMF。复发性 导致JAK-STAT通路异常激活的突变已被证明是JAK-STAT通路的驱动因素。 疾病因此，JAK抑制剂已被开发用于治疗PMF。然而，这些抑制剂只会减少 一些全身症状对致病性白血病干细胞（LSC）没有显著影响。一 对PMF发病机制的深入了解将为更好地治疗该疾病提供机会。的 骨髓生态位是PMF发病机制的关键组成部分。我们的初步数据显示 骨髓LepR+基质细胞是纤维化的来源。我们还确定了LepR+的几个关键介质 细胞纤维化在这个建议中，我们建议阐明LSC如何在细胞和分子机制， 与体内纤维化龛相互作用。我们将测试靶向纤维化介质是否会导致有效的 消除LSC并与JAK抑制剂具有协同作用。通过更深入地了解 LSC和生态位之间的相互作用，我们的靶向患病生态位的策略可以提供新的 治疗PMF。