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.

项目描述 我们的总体目标是了解紧急骨髓细胞生成是如何导致 骨髓恶性肿瘤，解剖潜在的代谢和表观遗传机制驱动异常自我再 恶性造血干细胞和祖细胞（HSPC）的新生和分化特性，并鉴定 潜在的弱点来治疗。在稳定状态下，血液生产反映了不同的亲- 罕见的静止造血干细胞（HSC）诱导少量骨髓偏向性多能产物， 多能祖细胞（MPP 2/3）和大量淋巴偏向性多能祖细胞（MPP 4），这两者都引起 粒细胞/巨噬细胞祖细胞（GMP），并导致有限的骨髓输出。相反，在重新- 第二代，激活的HSC过度产生骨髓偏向的MPP 2/3，淋巴偏向的MPP 4被重编程， GMP在骨髓腔中扩张为GMP簇（cGMP），驱动爆发 产生骨髓细胞。HSPC车厢的这种改造反映了紧急情况的参与， 骨髓生成途径，这是短暂激活再生过程中，但被增选，并不断 在骨髓恶性肿瘤如骨髓增生性肿瘤（MPN）中触发。然而，监管机构-- 控制紧急骨髓生成的疾病仍然知之甚少，白血病与骨髓增生异常综合征之间的关系 骨髓生成，其由MPN中的白血病前HSC持续提供燃料，以及再生性骨髓生成， 这是一种急性应激反应，目前还未被广泛研究。此外，紧急骨髓生成的作用 在急性髓性白血病（AML）的发展中，HSPC分化被阻断，白血病干细胞 细胞（LSC）从转化的HSPC中出现，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节自我更新和分化特性， 白血病骨髓生成在目标1中，我们将利用我们新产生的单细胞RNA测序 5-氟尿嘧啶（5 FU）介导的再生和Scl-tTA：TRE-BCR/ABL（BAtTA）MPN恶性肿瘤图谱，以确定 使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的调节过程（代谢适应和表观遗传）的作用。 重塑）在再生和恶性肿瘤期间驱动紧急骨髓生成。特别是，我们将测试 MYC转录因子、代谢产物α-酮戊二酸（αKG）和 HSPC室重构中的精氨酸溶解。在目标3中，我们将测试是否激活紧急情况 骨髓生成途径与白血病前HSC中的表观遗传驱动突变如TET 2缺失合作， 促进克隆选择和LSC从扩增和重塑的HSPC区室中出现。学院 当然，这些方法将揭示驱动紧急骨髓生成的机制，这些机制对疾病至关重要。 缓解发展，并提供新的见解，表观遗传和代谢状态相关的增强 骨髓细胞生成，这可能是白血病治疗的目标。