Project 4: Role and Function of Sphingomyelin Synthase 1 in Leukemia

项目4：鞘磷脂合酶1在白血病中的作用和功能

• 批准号: 10020940
• 负责人: CHIARA LUBERTO
• 金额: $ 19.8万
• 依托单位: STATE UNIVERSITY NEW YORK STONY BROOK
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-08-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10020940
• 关键词: Acute Megakaryocytic Leukemias; Acute Myelocytic Leukemia; Address; Aftercare; Anthracycline; Apoptosis; Cancer Biology; Cancer cell line; Cell Death Induction; Cell Line; Cell Proliferation; Cell Survival; Cell physiology; Cells; Ceramides; Chronic Myeloid Leukemia; Consumption; Cytarabine; Data; Diglycerides; Disease; Dose; Encyclopedias; Enzymes; Erythroblasts; Erythroid; GATA1 gene; Gene Expression; Genetic Transcription; Goals; Growth; Hematopoietic Neoplasms; Impairment; K-562; K562 Cells; Knowledge; Leukemic Cell; Link; Lipids; Maintenance; Malignant - descriptor; Malignant Neoplasms; Mediating; Megakaryoblast; Messenger RNA; Metabolic; Molecular; Patients; Pharmacology; Population; Probability; Production; Proteins; Publishing; Regulation; Residual Tumors; Resistance; Role; Sampling; Sphingolipids; Sphingosine; Testing; Therapeutic; Therapeutic Intervention; Work; acute myeloid leukemia cell; base; cancer cell; cancer therapy; chemotherapy; chronic myeloid leukemia cell; cytotoxic; effective therapy; erythroleukemic cell; improved; inhibitor/antagonist; leukemia; mouse model; neoplastic cell; new therapeutic target; novel; novel therapeutics; promoter; protein activation; protein kinase D; sphingomyelin synthase; treatment response

ABSTRACT The long-term goal of this project is to elucidate the role, regulation and therapeutic potential of sphingomyelin synthase (SMS) in cancer. The current proposal focuses on the function of SMS1 in growth of GATA1 positive leukemic cells (in particular, erythroblasts and megakaryoblasts) and on SMS1 as a potential novel therapeutic target in acute myeloid leukemias (AML) that are enriched in such malignant immature populations (particularly M6 and M7 AML). SMS represents a class of lipid-metabolizing enzymes that consumes ceramide and produces diacylglycerol (DAG), two critical bioactive lipids with opposing functions in the control of key cellular processes often dysregulated during transformation, including proliferation, apoptosis, and differentiation. Thus, SMS may be linked to cancer, but knowledge on SMS regulation and downstream functions is limited. We previously showed that elevated expression of SMS1 is critical for proliferation of erythroleukemic K562 cells. Published and preliminary results also show that the elevated expression of SMS1 is a consequence of enhanced transcription occurring through a novel alternative promoter positively regulated by the transcription factor GATA1. Guided by gene expression data from the Cancer Cell Line Encyclopedia, we discovered that the highest SMS1 expression (mRNA and protein) in blood cancer cells is found in GATA1 positive AML blasts (erythroblasts and megakaryoblasts). Importantly, pharmacological and molecular inhibition of SMS1 in these leukemic cells revealed a critical role for SMS1 in proliferation and survival of these cells that is not observed in GATA1-negative AML blasts. Thus, based on these observations, we hypothesize that SMS1 is an important novel regulator of proliferation and maintenance of GATA1 positive AMLs and a potential novel target for improving the dismal therapeutic response of these leukemias. To address our hypothesis, we will: 1. Determine the role and function of SMS1 in GATA1 positive AML cells and 2. Establish SMS1 as a novel target for therapeutic intervention against GATA1 positive AMLs. Our proposal aims at establishing SMS1 as a novel critical regulator of GATA1+ AML cells and might provide a molecularly informed, and much needed novel therapeutic option for treatment of AML with erythroid or megakaryocytic enrichment.

抽象的 该项目的长期目标是阐明 癌症中的鞘磷脂合酶（SMS）。当前的提案侧重于SMS1在增长中的功能 GATA1阳性白血病细胞（尤其是红细胞和巨型细胞），以及SMS1的潜力 急性髓样白血病（AML）中的新型治疗靶标，这些靶标在这种恶性不成熟中富含 种群（特别是M6和M7 AML）。 SMS代表一类脂肪代谢酶，可消耗神经酰胺并产生 二酰基甘油（DAG），两个关键的生物活性脂质在控制关键细胞过程中具有相反功能 在转化过程中通常会失调，包括增殖，凋亡和分化。因此，短信可能 与癌症有关，但是有关SMS调节和下游功能的知识是有限的。 我们先前表明，SMS1的表达升高对于促红血球的增殖至关重要 K562细胞。已发布和初步结果还表明，SMS1的表达升高是一个 通过通过新型替代启动子阳性调节转录的结果 转录因子GATA1。在癌细胞系百科全书中的基因表达数据的指导下，我们 发现在GATA1中发现了血液癌细胞中最高的SMS1表达（mRNA和蛋白质） 阳性AML爆炸（红细胞和巨型细胞）。重要的是，药理和分子 这些白血病细胞中SMS1的抑制作用揭示了SMS1在这些白血病细胞的增殖和存活中的关键作用 在GATA1阴性AML爆炸中未观察到的细胞。 因此，基于这些观察结果，我们假设SMS1是重要的新型调节剂 GATA1阳性AML的增殖和维持，也是改进的潜在新颖目标 这些白血病的治疗反应令人沮丧。为了解决我们的假设，我们将：1。确定角色 SMS1在GATA1阳性AML细胞中的功能和2。建立SMS1作为新的目标 针对GATA1阳性AML的治疗干预。 我们的建议旨在将SMS1建立为GATA1+ AML细胞的新型关键调节剂，并可能提供 分子知情，急需的新型治疗选择，用于用红细胞治疗AML或 巨核细胞富集。