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: 10094210
• 负责人: GUIDO MARCUCCI
• 金额: $ 51.06万
• 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/10094210
• 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/antagonist; 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)位于急性髓系白血病(AML)细胞的顶端 并具有无限自我更新和引发疾病的能力。寂静的人 部分LSCs提供了一个自我更新细胞的储存库，可以维持白血病的生长，防止 克隆性衰竭，并具有治疗耐药性；因此，消除LSCs是抗 白血病治疗。急性髓系白血病通过造成损失，深刻改变了骨髓(BM)的生态位 骨内膜骨髓中不可渗透的小动脉血管和可渗透的， 中央骨髓内有开窗的血窦血管。改建的BM利基市场允许LSC 扩张和白血病生长，但这种血管重塑的精细分子机制 仍有待充分阐明。MicroRNAs(MiRNAs)是靶向小的非编码RNA 信使RNA和调节蛋白质水平。MIR-126在静止状态下发挥着重要作用， 急性髓系白血病干细胞的自我更新与耐药最近我们发现miR-126主要是 表达于小动脉血管的SCA-1+内皮细胞(ECs)，负责 在BM利基市场供应MIR-126。正常情况下，miR-126由SCA-1+ECS提供 调节造血干细胞的动态平衡和活性。我们发现 急性髓细胞白血病原始分泌的肿瘤坏死因子α下调Sca-1+ECs miR-126的表达并导致小动脉丢失 船只。这导致对LSCs的miR-126供应减少，然后LSCs进入细胞周期 并诱导白血病的生长。我们还做了一个关键的观察，迫使miR-126下降- 调节低于BM白血病生态位中已经降低的水平(下称 MiR-126缺失)，导致进一步的小动脉丢失，这会损害LSCs，但不会损害正常的HSCs。 中和肿瘤坏死因子α恢复急性髓系白血病小鼠骨髓小动脉血运 LSC扩增而不是通过增加内皮细胞miR-126发挥抗白血病作用 供应给这些细胞。因此，这一提议的中心假设是，对 肿瘤坏死因子α诱导miR-126下调的细胞和分子基础及其对骨髓的影响 急性髓细胞白血病的血管重塑将使我们能够设计基于剥夺的新型miR-126治疗方法 这将消除对LSCs的动态平衡支持，使其容易受到抗白血病药物的攻击。 治疗。因此，我们提出了以下具体目标(SA)：SA#1：证明中心 肿瘤坏死因子α/miR-126轴在急性髓系白血病骨髓穴血管重构中的作用。SA#2： 明确肿瘤坏死因子α/miR-126轴在血管重塑中的分子机制 急性髓系白血病中的骨髓白血病小生境。SA#3：通过miR-1靶向白血病血管壁龛 126抑制剂与常用的抗白血病治疗相结合。