Cell-extrinsic emergency myelopoiesis regulated by ABCB7

ABCB7 调控的细胞外紧急骨髓细胞生成

• 批准号: 10675321
• 负责人: Kay Lynn Medina
• 金额: $ 32.28万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-15 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10675321
• 关键词: Address; Alleles; Anemia; Autoimmune Diseases; B cell differentiation; B-Cell Development; B-Lymphocytes; Bone Marrow; CD34 gene; Cell Lineage; Cells; Chronic; Compensation; DNA Damage; Data; Defect; Development; Disease; Dysmyelopoietic Syndromes; Emergency Situation; Engineering; Erythropoiesis; Exhibits; Exons; Generations; Grant; Hematology; Hematopoiesis; Hematopoietic; Human; Inflammation; Inflammation Mediators; Inner mitochondrial membrane; Iron Overload; Knock-out; Marrow; Mediating; Membrane Transport Proteins; Mus; Mutate; Mutation; Myelogenous; Myeloid Cells; Myelopoiesis; Myeloproliferative disease; Nonsense Codon; Nonsense-Mediated Decay; Patients; Population; RNA; RNA Splicing; Reporter; Risk; Role; Site; Spleen; Spliced Genes; Stimulus; Stress; Testing; Therapeutic; Transcript; Xenograft Model; bone loss; humoral immunity deficiency; mouse model; novel; precursor cell; progenitor; stem cells; systemic inflammatory response

Abstract Dysregulation of myelopoiesis can be either cell-intrinsic or cell-extrinsic. Cell-intrinsic mutations can result in myelodysplastic syndromes (MDSs) or myeloproliferative disorders (MPNs), while cell-extrinsic systemic inflammation promotes emergency myelopoiesis. However, the cause of the enhanced myelopoiesis is not always clear, and these two mechanisms are not necessarily mutually exclusive. Patients with chronic inflammation or autoimmune disease are at an increased risk for MDS, and chronic inflammation is often observed in MDS patients. Provocatively, our preliminary data demonstrates that a cell-extrinsic emergency myelopoiesis progressively develops when the inner mitochondrial membrane transporter ABCB7 is conditionally deleted in differentiating B cells in the bone marrow. ABCB7 is intrinsically required for B cell development beyond the pro-B cell stage. In 4-5 month old mice engineered to lack ABCB7 in B-lineage cells, bone marrow hematopoiesis is disrupted. Bone marrow erythropoiesis is dramatically reduced, and bone marrow myelopoiesis is greatly enhanced. To compensate for the loss of bone marrow marrow erythropoiesis, stress erythropoiesis is initiated in the spleen, however, the mice remain anemic. Importantly, the enhanced numbers of myeloid cells being produced in the bone marrow were not labelled with a cre-dependent reporter, establishing that the myeloid expansion is cell-extrinsic. ABCB7-deficient pro-B cells exhibit iron overload and DNA damage, which could provide the stimuli for initiation of chronic inflammation leading to progressive cell- extrinsic emergency myelopoiesis. Intriguingly, ABCB7 expression is decreased in myelodysplastic disorders in which patients have a mutation in the RNA splicing gene SF3B1. ABCB7 RNA levels are decreased by 60- 70% in SF3B1-mutated CD34+ cells from MDS-RS patients due to aberrant splicing and nonsense-mediated decay. We hypothesize that myelodysplasia in patients with SF3B1-mutated myelodysplastic disorders is not strictly cell-intrinsic, but instead there is a cell-extrinsic contribution mediated by decreased expression of ABCB7 in B-lineage precursor cells. To test this hypothesis, we have created a novel dox-regulated ABCB7 mouse model that allows us to address the hematopoietic consequences of decreased ABCB7 expression. These studies will establish that reduced expression of ABCB7, in both mouse and human hematopoiesis, leads to dysfunctional myelopoiesis due to B-lineage cells. Our studies will have important therapeutic implications for treating SF3B1-mutated myeloid disorders, as elimination of the B-lineage cells could contribute to amelioration of disease.

摘要 骨髓生成的失调既可以是细胞内的，也可以是细胞外的。细胞固有突变可导致 骨髓增生异常综合征(MDS)或骨髓增生性疾病(MPN)，而细胞-外源性全身 炎症促进了紧急的骨髓生成。然而，增强的骨髓生成的原因并不是 总是明确的，这两种机制不一定是相互排斥的。慢性阻塞性肺病患者 炎症或自身免疫性疾病增加了MDS的风险，慢性炎症通常 在MDS患者中观察到。具有挑衅性的是，我们的初步数据显示，一种细胞外源性紧急情况 当线粒体膜内转运体ABCB7 骨髓中B细胞分化过程中的条件性缺失。B细胞本质上需要ABCB7 超过前B细胞阶段的发育。在4-5个月大的小鼠中，基因工程使B系细胞中缺乏ABCB7， 骨髓的造血功能被打乱。骨髓红细胞生成显著减少，骨骼 骨髓的造血力大大增强。为了弥补骨髓红细胞生成的损失， 应激性红细胞生成始于脾，但小鼠仍处于贫血状态。重要的是，增强的 在骨髓中产生的髓系细胞的数量没有被cre依赖的报告分子标记， 证实髓系扩张是细胞外源性的。ABCB7缺陷的Pro-B细胞表现出铁超载和 DNA损伤，这可能为慢性炎症的启动提供刺激，导致进行性细胞- 外源性的紧急骨髓生成。有趣的是，ABCB7在骨髓增生异常疾病中的表达降低 其中患者的RNA剪接基因SF3B1发生突变。ABCB7RNA水平降低了60%- MDS-RS患者SF3B1突变的CD34+细胞中70%是由于异常剪接和无义介导 腐烂。我们假设SF3B1突变的骨髓增生性疾病患者的骨髓发育不良不是 严格地说是细胞固有的，但相反，有一种细胞外部贡献是通过减少表达的 B系前体细胞中的ABCB7。为了验证这一假设，我们创建了一个新的DOX调节的ABCB7 小鼠模型，使我们能够解决ABCB7表达减少的造血后果。 这些研究将证实，ABCB7在小鼠和人类造血系统中的表达减少， 导致B系细胞功能障碍的骨髓生成。我们的研究将具有重要的治疗作用 对治疗SF3B1突变的髓系疾病的意义，因为消除B系细胞可能 为改善疾病作出贡献。