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）位于急性髓性白血病（AML）细胞的顶端， 等级制度，并具有无限自我更新和引发疾病的能力。静态 LSC的一部分提供了自我更新细胞的储存库，这些细胞维持白血病生长，预防白血病， 克隆衰竭，并且是治疗抗性的;因此消除LSC是抗- 白血病治疗AML原始细胞通过引起丢失而深刻地改变骨髓（BM）生态位 非渗透性小动脉血管的骨内膜骨髓和丰富的渗透性， 中央骨髓中的有孔窦状血管。重塑的BM龛允许LSC 扩张和白血病生长，但这种血管重塑的精细分子机制 还有待于充分阐明。microRNAs（miRNAs）是一种非编码的小分子RNA， 信使RNA和调节蛋白质水平。miR-126在静止期起重要作用， AML LSC的自我更新和耐药性。最近，我们发现miR-126主要是 在小动脉血管的Sca-1+内皮细胞（EC）中表达，其负责 在BM小生境中提供miR-126。在正常条件下，来自Sca-1+ EC的miR-126供应 调节造血干细胞（HSC）的稳态和活性。我们发现 AML原始细胞分泌的TNFα下调Sca-1+ EC中的miR-126，并导致小动脉内皮细胞减少。 船舶.这导致miR-126向LSC的供应减少，然后LSC参与细胞周期 并诱导白血病生长。我们还做了“关键”的观察，迫使miR-126下降- 调节低于BM白血病小生境中已经降低的水平（下文称为“调节”）。 “miR-126剥夺”）导致小动脉的进一步损失，这损害LSC而不是正常HSC。 通过中和TNFα恢复AML小鼠BM小动脉血管化有利于静止 LSC扩增而不是通过增加内皮miR-126而具有抗白血病作用 供给这些细胞。因此，这一建议的中心假设是， TNFα诱导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的基于miR-126剥夺的治疗方法 这将消除对LSC的稳态支持，使它们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 TNFα/miR-126轴在AML BM白血病小生境血管重塑中的作用SA #2： 明确TNFα/miR-126轴在血管重构中的分子机制， 急性髓细胞白血病中的骨髓白血病生态位。SA#3：miR-121对白血病血管小生境的治疗靶向作用 126抑制剂与常用的抗白血病疗法组合。