Vascular Remodeling in the Bone Marrow Leukemic Niche: A Therapeutic Target?

骨髓白血病微环境中的血管重塑：治疗目标？

• 批准号: 10371023
• 负责人: GUIDO MARCUCCI
• 金额: $ 50.04万
• 依托单位: BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10371023
• 关键词: Acute Myelocytic Leukemia; Anatomy; Apoptosis; Azacitidine; BCL2 gene; Binding; Biology; Blast Cell; Blood Vessels; Bone Marrow; Bone remodeling; Cell Cycle; Cells; Cities; Clinic; Clinical; Clinical Trials; Discontinuous Capillary; Disease; Down-Regulation; Drug resistance; Endothelial Cells; Endothelium; FLT3 gene; Growth; Hematopoietic stem cells; Homeostasis; Human; Left; Marrow; Messenger RNA; MicroRNAs; Modeling; Molecular; Molecular Cytogenetics; Mus; Patients; Permeability; Play; Proliferating; Proteins; Resistance; Role; TNF gene; Testing; Toxicology; Tyrosine Kinase Inhibitor; Untranslated RNA; Vascular remodeling; Vascularization; arteriole; base; calmodulin-dependent protein kinase II; cell growth; chemotherapy; cytokine; deprivation; design; effective therapy; exhaustion; improved outcome; in vivo; inhibitor; innovation; insight; leukemia; leukemia treatment; leukemic stem cell; new therapeutic target; novel; patient derived xenograft model; pre-clinical; prevent; self renewing cell; self-renewal; stem cell expansion; therapeutic target; trafficking

Leukemia stem cells (LSCs) are at the apex of the acute myeloid leukemia (AML) cellular hierarchy and have the capability of unlimited self-renewal and of initiating disease. The quiescent fraction of LSCs provides a reservoir of self-renewing cells that sustain leukemia growth, prevent clonal exhaustion, and are treatment resistant; thus eliminating LSCs is the “holy grail” of anti- leukemia treatment. AML blasts profoundly modify the bone marrow (BM) niche by causing loss of non-permeable arteriolar vessels in the endosteal marrow and enrichment of permeable, fenestrated sinusoid vessels in the central marrow. The remodeled BM niche is permissive of LSC expansion and leukemia growth, yet the fine molecular mechanisms of this vascular remodeling remain to be fully elucidated. MicroRNAs (miRNAs) are small non-coding RNAs that target messenger RNAs and regulate protein levels. miR-126 plays an important role in quiescence, self-renewal and drug resistance of AML LSCs. Recently we showed that miR-126 is mostly expressed in the Sca-1+ endothelial cells (ECs) of arteriolar vessels, which are responsible for supplying miR-126 in the BM niche. Under normal conditions, miR-126 supply from Sca-1+ ECs regulates the homeostasis and activity of hematopoietic stem cells (HSCs). We discovered that AML blast-secreted TNFα down-regulates miR-126 in Sca-1+ ECs and causes a loss of arteriolar vessels. This results in a decreased supply of miR-126 to LSCs, which then engage the cell cycle and induce leukemia growth. We also made the “key” observation that forcing miR-126 down- regulation below the already decreased levels in the BM leukemic niche (hereafter referred to as “miR-126 deprivation”), leads to further loss of arterioles which harms LSCs but not normal HSCs. Restoring BM arteriolar vascularization in AML mice by neutralization of TNFα favors quiescent LSC expansion rather than having an antileukemic effect by increasing endothelial miR-126 supply to these cells. Thus, the central hypothesis of this proposal is that the understanding of the cellular and molecular basis of TNFα-induced miR-126 downregulation and its impact on BM vascular remodeling in AML will allow us to design novel miR-126 deprivation-based treatments that will eliminate homeostatic support to LSCs, rendering them vulnerable to anti-leukemic therapies. Therefore, we propose the following Specific Aims (SAs): SA#1: To prove the central role of the TNFα/miR-126 axis in vascular remodeling of the BM leukemic niche in AML. SA#2: Define the molecular mechanisms of the TNFα/miR-126 axis in the vascular remodeling of the BM leukemic niche in AML. SA#3: Therapeutic targeting of the leukemic vascular niche by a miR- 126 inhibitor in combination with commonly used antileukemic therapies.

白血病干细胞（LSC）在急性髓样白血病（AML）细胞的顶点 层次结构，具有无限自我更新和引发疾病的能力。静止 LSC的一部分提供了维持白血病生长的自我更新细胞的水库，防止 克隆疲惫，具有耐药性；因此，消除LSC是反 - 白血病治疗。 AML通过造成损失，深刻地爆炸了骨髓（BM）小众 内骨骨髓中不可渗透的小动脉血管的富集 中央骨髓中的吞噬正弦血管。重塑的BM利基市场允许LSC 膨胀和白血病的生长，但这种血管重塑的精细分子机制 保持充分阐明。 microRNA（miRNA）是针对的小非编码RNA 信使RNA和调节蛋白质水平。 miR-126在静止中起重要作用， AML LSC的自我更新和耐药性。最近我们表明miR-126主要是 在小动脉血管的SCA-1+内皮细胞（EC）中表达，该血管负责 在BM利基市场中提供miR-126。在正常条件下，SCA-1+ EC的miR-126供应 调节造血干细胞（HSC）的体内平衡和活性。我们发现了这一点 AML爆炸分泌的TNFα下调SCA-1+ EC中的miR-126，并导致小动脉损失 船只。这导致MiR-126供应减少到LSC，然后参与细胞周期 并诱导白血病生长。我们还做出了“关键”观察，即强迫mir-126下降 - 低于BM白血病利基市场已经提高水平的法规（以下称为 “ miR-126剥夺”），导致动脉进一步损失，这会损害LSC，但不是正常的HSC。 通过中和TNFα的最爱静止 LSC扩展而不是通过增加内皮miR-126具有抗白血病作用 向这些细胞供应。那就是这一提议的核心假设是对 TNFα诱导的miR-126下调的细胞和分子基础及其对BM的影响 AML中的血管重塑将使我们能够设计新型的miR-126基于剥夺的疗法 这将消除对LSC的稳态支持，使它们容易受到抗Leukemic的影响 疗法。因此，我们提出以下特定目标（SAS）：SA＃1：证明中央 TNFα/miR-126轴在AML中BM白血病生态位的血管重塑中的作用。 SA＃2： 在血管重塑中定义TNFα/miR-126轴的分子机制 AML中的BM白血病利基市场。 SA＃3：通过miR-的治疗性靶向白血病血管生态位 126抑制剂与常用的抗肺血症疗法结合使用。