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.

抽象的 骨髓生成失调可以是细胞内在的，也可以是细胞外在的。细胞内在突变可导致 骨髓增生异常综合征 (MDS) 或骨髓增殖性疾病 (MPN)，而细胞外源性系统性 炎症促进紧急骨髓细胞生成。然而，骨髓生成增强的原因并不是 总是很清楚，并且这两种机制不一定是相互排斥的。慢性病患者 炎症或自身免疫性疾病会增加患 MDS 的风险，而慢性炎症通常是 在 MDS 患者中观察到。令人兴奋的是，我们的初步数据表明，细胞外的紧急情况 当线粒体内膜转运蛋白 ABCB7 处于正常状态时，骨髓细胞生成逐渐发展。 在骨髓中分化的 B 细胞中被条件性删除。 ABCB7 是 B 细胞本质上所必需的 发育超出原 B 细胞阶段。在 4-5 个月大的小鼠中，B 系细胞中缺乏 ABCB7， 骨髓造血被破坏。骨髓红细胞生成急剧减少，骨 骨髓造血功能大大增强。为了补偿骨髓红细胞生成的损失， 应激性红细胞生成在脾脏中启动，然而，小鼠仍然贫血。重要的是，增强型 骨髓中产生的骨髓细胞数量没有用依赖于 cre 的报告基因标记， 确定骨髓扩张是细胞外源性的。 ABCB7 缺陷的亲 B 细胞表现出铁过载和 DNA 损伤，可能会刺激慢性炎症的发生，从而导致进行性细胞损伤 外源性紧急骨髓生成。有趣的是，ABCB7 表达在骨髓增生异常性疾病中降低 其中患者的 RNA 剪接基因 SF3B1 发生突变。 ABCB7 RNA 水平降低 60- 来自 MDS-RS 患者的 SF3B1 突变 CD34+ 细胞中有 70% 是由于异常剪接和无义介导所致 衰变。我们假设 SF3B1 突变的骨髓增生异常疾病患者的骨髓增生异常不是 严格来说是细胞内在的，但相反，存在由细胞表达减少介导的细胞外在贡献 B 系前体细胞中的 ABCB7。为了验证这一假设，我们创建了一种新型 dox 调控的 ABCB7 小鼠模型使我们能够解决 ABCB7 表达减少的造血后果。 这些研究将确定小鼠和人类造血过程中 ABCB7 的表达减少， 由于 B 系细胞导致骨髓生成功能障碍。我们的研究将具有重要的治疗作用 对治疗 SF3B1 突变骨髓疾病的影响，因为消除 B 谱系细胞可以 有助于疾病的改善。