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 骨髓生成失调可以是细胞内源性的或细胞外源性的。细胞内在突变可导致 骨髓增生异常综合征（MDS）或骨髓增生性疾病（MPN），而细胞外系统性 炎症促进紧急骨髓生成。然而，骨髓生成增强的原因不是 这两种机制并不一定是相互排斥的。慢性 炎症或自身免疫性疾病增加了MDS的风险， 在MDS患者中观察到。具有挑衅性的是，我们的初步数据表明， 当线粒体内膜转运蛋白ABCB 7被激活时，骨髓生成进行性发展。 在骨髓中的分化B细胞中有条件地缺失。ABCB 7是B细胞的内在要求 B细胞阶段之后的发展。在4-5个月大的小鼠中，工程改造为在B系细胞中缺乏ABCB 7， 骨髓造血被破坏。骨髓红细胞生成显著减少， 骨髓造血大大增强。为了弥补骨髓红细胞生成的损失， 应激性红细胞生成在脾中开始，然而，小鼠仍然贫血。重要的是，增强 在骨髓中产生的髓样细胞的数量没有用CREE依赖性报道分子标记， 确定骨髓扩增是细胞外的。ABCB 7缺陷型前B细胞表现出铁过载， DNA损伤，这可能会提供刺激，引发慢性炎症，导致进行性细胞- 外源性紧急骨髓生成有趣的是，骨髓增生异常疾病中ABCB 7表达减少 其中患者在RNA剪接基因SF 3B 1中有突变。ABCB 7 RNA水平降低60- 在MDS-RS患者的SF 3B 1突变的CD 34+细胞中，由于异常剪接和无义介导的 腐烂我们假设SF 3B 1突变的骨髓增生异常疾病患者的骨髓增生异常不是 严格的细胞内在的，但相反，有一个细胞外在的贡献介导的表达减少， B系前体细胞中的ABCB 7。为了验证这一假设，我们创造了一种新的dox调节的ABCB 7。 小鼠模型，使我们能够解决ABCB 7表达减少的造血后果。 这些研究将确定小鼠和人造血中ABCB 7的表达降低， 导致B系细胞引起的骨髓生成功能障碍。我们的研究将对治疗 对治疗SF 3B 1突变的骨髓疾病的意义，因为B系细胞的消除可以 有助于改善疾病。