Emergency Myelopoiesis in the Pathogenesis of Myeloid Malignancies

骨髓恶性肿瘤发病机制中的紧急骨髓生成

基本信息

批准号：
10298484
负责人：
Emmanuelle Passegue
金额：
$ 54.79万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-01 至 2026-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10298484
关键词：
Acute Myelocytic Leukemia Address Atlases Automobile Driving Biological Assay Biology Blast Cell Blood Bone Marrow Bone Marrow Purging CSF3 gene Cell Compartmentation Cell Differentiation process Cells Chromatin Chronic Myeloid Leukemia Clone Cells Comparative Study Complex Consumption Dependence Development Disadvantaged Disease Disease Progression Emergency Situation Enzymes Epigenetic Process Fluorouracil Generations Genes Genetic Genetic Transcription Goals Hematopoietic stem cells Impairment Inflammation Interleukin-1 Interleukin-6 Investigation Laboratories Lymphoid Lymphopoiesis MPP3 gene Maintenance Malignant - descriptor Malignant Neoplasms Mediating Megakaryocytes Metabolic Modeling Molecular Multipotent Stem Cells Myelofibrosis Myelogenous Myeloid Cells Myeloid Leukemia Myelopoiesis Myeloproliferative disease Natural regeneration Output Pathogenesis Pathway interactions Patients Phase Play Population Process Production Property Proto-Oncogene Proteins c-myc Regulation Role Signal Transduction TNF gene Testing Transforming Growth Factor beta Transplantation Work acute stress alpha ketoglutarate bcr-abl Fusion Proteins beta catenin biological adaptation to stress cytokine driver mutation epigenetic regulation granulocyte hematopoietic stem cell quiescence improved insight leukemia leukemia treatment leukemic stem cell macrophage metabolomics mitochondrial metabolism mouse model notch protein novel novel strategies novel therapeutics osteoprogenitor cell prevent progenitor regenerative self-renewal single-cell RNA sequencing stem cell function targeted treatment

项目摘要

PROJECT DESCRIPTION Our overall goals are to understand how emergency myelopoiesis contributes to the pathogenesis of myeloid malignancies, dissect the underlying metabolic and epigenetic mechanisms driving aberrant self-re- newal and differentiation properties in malignant hematopoietic stem and progenitor cells (HSPC), and identify potential vulnerabilities to target therapeutically. At steady-state, blood production reflects the differential pro- duction by rare quiescent hematopoietic stem cells (HSC) of a small number of myeloid-biased multipotent pro- genitors (MPP2/3) and a large number of lymphoid-biased multipotent progenitors (MPP4), which both give rise to granulocyte/macrophage progenitors (GMP) and contribute to limited myeloid output. In contrast, during re- generation, activated HSCs overproduce myeloid-biased MPP2/3, lymphoid-biased MPP4 are reprogrammed towards myelopoiesis, and GMP expand in the bone marrow (BM) cavity as GMP clusters (cGMP), driving burst production of myeloid cells. This remodeling of the HSPC compartment reflects the engagement of emergency myelopoiesis pathways, which are transiently activated during regeneration but are co-opted and constantly triggered in myeloid malignancies such as myeloproliferative neoplasms (MPN). However, the regulatory mech- anisms controlling emergency myelopoiesis remain poorly understood, and the relationships between leukemic myelopoiesis, which is continuously fueled by pre-leukemic HSCs in MPNs, and regenerative myelopoiesis, which is an acute stress response, are still largely unexplored. Furthermore, the role of emergency myelopoiesis in the development of acute myeloid leukemia (AML), where HSPC differentiation is blocked and leukemic stem cells (LSC) emerges from transformed HSPCs, remains unknown. Our objective is to identify how HSPCs adapt in these different situations and adjust both self-renewal and differentiation properties during regenerative and leukemic myelopoiesis. In Aim 1, we will take advantage of our newly generated single-cell RNA sequencing atlas of 5-fluorouracil (5FU)-mediated regeneration and Scl-tTA:TRE-BCR/ABL (BAtTA) MPN malignancy to iden- tify changes in cell-state and differentiation trajectories driving activation of emergency myelopoiesis pathways. In Aim 2, we will investigate the role of two key regulatory processes (metabolic adaptation and epigenetic remodeling) in driving emergency myelopoiesis during regenerative and malignancy. In particular, we will test the central role of the MYC transcription factor, the metabolite alpha-ketoglutarate (αKG) and the process of glutaminolysis in remodeling the HSPC compartment. In Aim 3, we will test whether activation of emergency myelopoiesis pathways cooperates with epigenetic driver mutations like TET2 loss in pre-leukemic HSCs to promote clonal selection and LSC emergence from an expanded and remodeled HSPC compartment. Collec- tively, these approaches will uncover the mechanisms driving emergency myelopoiesis that are critical for dis- ease development, and provide new insights into the epigenetic and metabolic states associated with enhanced myelopoiesis that could potentially be targeted for leukemia treatment.

项目描述我们的总体目标是了解紧急骨髓生成如何促进骨髓增生异常综合征的发病机制骨髓恶性肿瘤，剖析驱动异常自我重组的潜在代谢和表观遗传机制恶性造血干细胞和祖细胞 (HSPC) 的新特性和分化特性，并鉴定在稳态下，血液产量反映了治疗目标的潜在脆弱性。由罕见的静态造血干细胞（HSC）诱导少数骨髓偏向的多能亲细胞生殖细胞 (MPP2/3) 和大量淋巴偏向的多能祖细胞 (MPP4)，两者均产生粒细胞/巨噬细胞祖细胞 (GMP) 并导致有限的骨髓输出。一代，激活的 HSC 过度产生骨髓偏向的 MPP2/3，淋巴偏向的 MPP4 被重新编程骨髓生成，并且 GMP 在骨髓 (BM) 腔中以 GMP 簇 (cGMP) 形式扩展，驱动爆发 HSPC 室的这种重塑反映了紧急情况的发生。骨髓生成途径，在再生过程中短暂激活，但不断被选择然而，骨髓增生性肿瘤 (MPN) 等骨髓恶性肿瘤中会引发这种情况。控制紧急骨髓生成的无性现象仍然知之甚少，并且白血病之间的关系骨髓生成，由 MPN 中的白血病前 HSC 持续推动，以及再生性骨髓生成，这是一种急性应激反应，但紧急骨髓生成的作用在很大程度上仍未被探索。在急性髓系白血病 (AML) 的发展过程中，HSPC 分化受阻，白血病干细胞细胞 (LSC) 从转化的 HSPC 中产生，仍然未知，我们的目标是确定 HSPC 如何适应。在这些不同的情况下，并在再生和分化过程中调整自我更新和分化特性在目标 1 中，我们将利用我们新生成的单细胞 RNA 测序。 5-氟尿嘧啶 (5FU) 介导的再生和 Scl-tTA:TRE-BCR/ABL (BAtTA) MPN 恶性肿瘤的图谱细胞状态和分化轨迹的变化驱动紧急骨髓生成途径的激活。在目标 2 中，我们将研究两个关键调控过程（代谢适应和表观遗传）的作用。特别是，我们将测试在再生和恶性肿瘤期间驱动紧急骨髓生成的作用。 MYC 转录因子、代谢物 α-酮戊二酸 (αKG) 的核心作用以及谷氨酰胺分解在重塑 HSPC 隔室中的作用在目标 3 中，我们将测试是否激活紧急情况。骨髓生成途径与表观遗传驱动突变（例如白血病前 HSC 中的 TET2 缺失）合作，促进克隆选择和 LSC 从扩展和改造的 HSPC 隔室中出现。积极地，这些方法将揭示驱动紧急骨髓生成的机制，这对于疾病的治疗至关重要。简化开发，并为与增强相关的表观遗传和代谢状态提供新的见解骨髓细胞生成可能成为白血病治疗的目标。