Cell-extrinsic emergency myelopoiesis regulated by ABCB7

ABCB7 调控的细胞外紧急骨髓细胞生成

基本信息

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
项目类别：
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

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

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项目摘要

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.

抽象的脊髓脉的失调可能是细胞内膜或细胞脱骨。细胞中性突变可能导致骨髓增生综合征（MDS）或骨髓增生性疾病（MPN），而细胞超支全身性炎症会促进紧急脊髓脉。但是，增强的骨髓病的原因不是始终清楚，这两种机制不一定是互斥的。慢性患者炎症或自身免疫性疾病的风险增加，慢性炎症通常是在MDS患者中观察到。挑衅地，我们的初步数据表明细胞超紧急当内部线粒体膜转运蛋白ABCB7是有条件地在骨髓中的分化B细胞中删除。 B细胞本质上需要ABCB7 超出Pro-B细胞阶段的发展。在4-5个月大的小鼠中，在B-linege细胞中缺乏ABCB7，骨髓造血症受到干扰。骨髓红细胞生成大大减少，骨头骨髓骨髓菌有大大增强。为了弥补骨髓骨髓红细胞生成的损失，脾脏在脾脏中启动了压力红细胞生成，但是，小鼠仍然贫血。重要的是，增强了在骨髓中产生的髓样细胞数量没有用CRE依赖的记者标记确定髓样膨胀是细胞效果。 ABCB7缺陷的pro-B细胞表现出铁超载和 DNA损伤，这可以为引发慢性炎症的刺激，从而导致进行性细胞 - 外部紧急骨髓骨膜外。有趣的是，ABCB7表达在骨髓塑性疾病中降低其中患者在RNA剪接基因SF3B1中有突变。 ABCB7 RNA水平降低60- 由于剪接和废话介导的，来自MDS-RS患者的SF3B1突变的CD34+细胞中的70％衰变。我们假设SF3B1突变的骨髓增生性疾病的患者中的骨髓增生不是严格的细胞中性，但相反，有一个细胞 - 超支贡献是通过降低的表达介导的 B-Linege前体细胞中的ABCB7。为了检验这一假设，我们创建了一个新颖的DOX调节的ABCB7 小鼠模型使我们能够解决降低ABCB7表达的造血后果。这些研究将确定，在小鼠和人造血中，ABCB7的表达降低，由于B型细胞导致功能失调的脊髓脉虫素。我们的研究将具有重要的治疗性对治疗SF3B1氧化的髓样疾病的影响，因为消除了B-linege细胞有助于改善疾病。