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造成紧急造成的造影髓样恶性肿瘤，剖析驱动异常自我的基本代谢和表观遗传机制恶性造血茎和祖细胞（HSPC）的新和分化特性，并鉴定靶向治疗的潜在脆弱性。在稳态，血液产生反映了差异促值少数髓样偏置的多能促值的稀有静脉造血干细胞（HSC）的作用生殖器（MPP2/3）和大量淋巴偏置的多能祖细胞（MPP4），它们都会产生到粒细胞/巨噬细胞祖细胞（GMP），并导致有限的髓样输出。相反，在重新生成，激活的HSC过量产生髓样偏置的MPP2/3，淋巴偏见的MPP4被重新编程朝向脊髓虫，GMP作为GMP簇（CGMP）在骨髓（BM）腔中膨胀，驾驶爆发产生髓样细胞。 HSPC隔间的这种改建反映了紧急情况的参与髓鞘途径，在再生期间瞬时激活，但被选为并不断地激活在髓样恶性肿瘤中触发，例如骨髓增生性肿瘤（MPN）。但是，监管机械 - 控制紧急脊髓疾病的anisms仍然很众所周知，白血病之间的关系骨髓虫在MPN中不断地被白细胞的HSC和再生性骨髓虫卵这是一种急性应力反应，仍然是出乎意料的。此外，紧急骨髓膜的作用在急性髓样白血病（AML）的发展中，HSPC分化被阻断和白血病茎细胞（LSC）来自转化后的HSPC，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，并调整再生期间的自我更新和分化特性白血病脊髓疾病。在AIM 1中，我们将利用新生成的单细胞RNA测序 5-氟尿嘧啶（5FU）介导的再生和SCL-TTA的地图集：tre-bcr/abl（batta）mpn恶性肿瘤研究细胞态和分化轨迹的变化，驱动紧急骨髓虫途径的激活。在AIM 2中，我们将研究两个关键调节过程的作用（代谢适应和表观遗传学重塑）在再生和恶性肿瘤期间驾驶紧急脊髓疾病。特别是，我们将测试 MYC转录因子，代谢物α-酮戊二酸（αkg）的核心作用和谷氨酰胺溶解在重塑HSPC室中。在AIM 3中，我们将测试是否激活紧急脊髓疾病途径与表观遗传驱动器突变（如Leukemic HSC中的TET2损失）合作从扩展和重塑的HSPC室促进克隆选择和LSC出现。收集- 从表面上讲，这些方法将发现驱动紧急骨髓性的机制，这些机制对于解散至关重要简化开发，并提供有关与增强相关的表观遗传和代谢状态的新见解可能针对白血病治疗的脊髓虫。