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

• 批准号: 10457443
• 负责人: Emmanuelle Passegue
• 金额: $ 53.69万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 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/10457443
• 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

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.

项目说明 我们的总体目标是了解紧急骨髓生成如何在急性髓系白血病的发病机制中起作用。 髓系恶性肿瘤，解剖潜在的代谢和表观遗传机制，驱动异常的自我再... 恶性造血干/祖细胞(HSPC)的新特性和分化特性 潜在的针对治疗的弱点。在稳定状态下，血液产量反映了不同的比例。 少见的静止造血干细胞对少量髓系偏向多能干细胞的诱导作用 基因(MPP2/3)和大量偏向淋巴系的多能祖细胞(MPP4)，两者都能产生 向粒细胞/巨噬细胞祖细胞(GMP)转化，并导致有限的髓系输出。相比之下，在重新- 生成，激活的HSC过度产生偏向髓系的MPP2/3，偏向淋巴系的MPP4被重新编程 走向骨髓生成，GMP以GMP簇(CGMP)的形式在骨髓腔内扩张，驱动爆裂 髓系细胞的产生。HSPC车厢的这种改建反映了紧急情况下的参与 骨髓生成途径，在再生过程中被短暂激活，但被选择性地持续存在 在髓系恶性肿瘤中触发，如骨髓增生性肿瘤(MPN)。然而，监管机制- 控制紧急骨髓生成的失调症仍然知之甚少，白血病与 骨髓生成，这是由MPN中的白血病前期HSCs持续推动的，以及再生的骨髓生成， 这是一种急性应激反应，在很大程度上仍未被探索。此外，紧急骨髓生成的作用 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)是从转化的HSPC中产生的，目前尚不清楚。我们的目标是确定HSPC如何适应 在这些不同的情况下，调整自我更新和分化特性在再生和 白血病的骨髓生成。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)介导的再生与SCL-TTA：TrE-BCR/ABL(Batta)MPN恶性转化的研究 确定细胞状态和分化轨迹的变化，以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 重塑)在再生和恶性过程中驱动紧急的骨髓生成。特别是，我们将测试 MYC转录因子，代谢物α-酮戊二酸(αKG)的中心作用和 HSPC室改建中的谷氨酰胺分解作用。在目标3中，我们将测试紧急情况的激活 骨髓生成途径与表观遗传驱动突变(如白血病前期HSCTET2缺失)协同作用 促进克隆选择和LSC从扩大和改建的HSPC隔间涌现。科莱克- 从本质上讲，这些方法将揭示推动紧急骨髓生成的机制，这些机制对疾病至关重要。 简化开发，并提供有关增强的表观遗传和代谢状态的新见解 有可能成为白血病治疗靶点的骨髓生成。