Mechanisms of Formation and Progression of Preleukemic Stem Cells

白血病前期干细胞的形成和进展机制

• 批准号: 9331278
• 负责人: Ulrich Steidl
• 金额: $ 39.74万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE, INC
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-01 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9331278
• 关键词: Acute Myelocytic Leukemia; Address; Affect; Automobile Driving; Binding; Binding Sites; Biological; Cancerous; Cause of Death; Cell physiology; Cells; Chromatin; Combination Drug Therapy; Data; Disease; Dysmyelopoietic Syndromes; Enhancers; Epigenetic Process; Failure; Genetic Transcription; Goals; Hematopoietic; Hematopoietic stem cells; Human; Impairment; In Vitro; Knowledge; Lead; Leukemic Cell; Longitudinal Studies; Maintenance; Mediating; Minor Groove; Modeling; Molecular; Mus; Mutate; Mutation; Pathway interactions; Patients; Pharmacology; Phenotype; Play; Premalignant; Premalignant Cell; Relapse; Reporting; Research; Role; Sampling; Stem cells; Testing; base; cancer cell; chemotherapy; disease heterogeneity; human disease; improved; in vivo; inhibitor/antagonist; leukemia; mouse model; novel; novel strategies; novel therapeutics; older patient; prospective; response; small hairpin RNA; small molecule; targeted treatment; transcription factor; treatment strategy

ABSTRACT Despite frequent initial response to chemotherapy, overall cure rates have remained below 20% in patients with AML for the past 45 years, and relapse continues to be the most common cause of death. Recent evidence has shown that the accumulation of stepwise genetic and epigenetic changes in HSC lead to the formation of pre- leukemic stem cells (pre-LSC) that play a pivotal role not only in disease origination but also in leukemia relapse. While the existence and essentiality of such pre-cancerous cell states has been demonstrated in mice and humans, very little is known about the molecular mechanisms driving pre-LSC formation and progression. The transcription factor PU.1 is frequently heterozygously mutated or otherwise impaired in patients with AML. We have recently reported a mouse model of preleukemic-to-AML progression molecularly driven by heterozygous PU.1 enhancer deletion. This novel model is characterized by definable, functionally altered pre- leukemic stem cells and closely resembles human disease in key molecular, cell biological, and phenotypic features, including disease heterogeneity. This model now permits the identification and functional study of mechanisms driving the formation and progression of pre-leukemic stem cells. Furthermore, we have obtained proof-of-concept that PU.1-low AML cells show an increased vulnerability to further PU.1 inhibition (as complete loss of PU.1 leads to stem cell and hematopoietic failure), and we have developed first-in-class small- molecule pharmacologic inhibitors of PU.1, which directly interfere with PU.1-chromatin binding. Strikingly, we found that PU.1 inhibition by shRNA or small molecules has significant inhibitory effects on AML cells, including at the level of leukemia-initiating cells, while only minimally affecting normal HSC. PU.1 inhibition thus represents a new potential strategy to target AML. Based on our recent findings we propose to: 1. Identify and study pathways that are functionally critical for pre- LSC formation and maintenance; 2. Identify pathways that trigger the preleukemic-to-leukemic “switch”, and progression of pre-LSC to different AML subtypes (mature/immature/bi-lineage), thus causing disease heterogeneity; 3. Study the mechanisms underlying the anti-leukemic effects of PU.1 inhibition in AML cells. We will employ our novel murine AML preLSC-to-LSC transition model as well as primary human MDS/AML samples. We will longitudinally study molecular changes at the stem cell level and functionally test dysregulated candidate pathways in vitro and in vivo. Furthermore, we will use shRNA and our novel drugs to identify PU.1 targets that mediate the anti-leukemic effects of PU.1 inhibition in AML cells. In summary, our study will improve our molecular understanding of pre-cancerous/leukemic cell states and their progression to fully transformed AML. Furthermore, our study will extend our proof-of-concept and understanding of PU.1 inhibition as a novel therapeutic strategy for the treatment of AML and at the pre-LSC level, a completely new approach in AML with considerable translational potential.

摘要