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

基本信息

批准号：
10469606
负责人：
CHIARA LUBERTO
金额：
$ 19.4万
依托单位：
STATE UNIVERSITY NEW YORK STONY BROOK
依托单位国家：
美国
项目类别：
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/10469606
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 leukemia mouse model neoplastic cell new therapeutic target novel novel therapeutics promoter protein activation protein kinase D sphingomyelin synthase treatment response

项目摘要

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其作用、调节和治疗潜力鞘磷脂合酶（SMS）在癌症中的作用。目前的提案重点关注 SMS1 在增长方面的功能 GATA1 阳性白血病细胞（特别是成红细胞和巨核细胞）和 SMS1 作为潜在的急性髓系白血病（AML）的新治疗靶点富含此类恶性未成熟细胞人群（特别是 M6 和 M7 AML）。 SMS代表一类脂质代谢酶，它消耗神经酰胺并产生二酰基甘油 (DAG) 是两种关键的生物活性脂质，在控制关键细胞过程中具有相反的功能在转化过程中经常失调，包括增殖、凋亡和分化。因此，短信可以与癌症有关，但有关短信调节和下游功能的知识有限。我们之前表明 SMS1 的表达升高对于红白血病细胞的增殖至关重要 K562细胞。已发表的初步结果还表明 SMS1 的表达升高是通过正向调节的新型替代启动子发生增强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，我们发现血癌细胞中最高的 SMS1 表达（mRNA 和蛋白质）存在于 GATA1 中阳性 AML 母细胞（成红细胞和巨核细胞）。重要的是，药理学和分子在这些白血病细胞中抑制 SMS1 揭示了 SMS1 在这些白血病细胞的增殖和存活中发挥着关键作用。在 GATA1 阴性 AML 母细胞中未观察到的细胞。因此，基于这些观察，我们假设 SMS1 是一种重要的新型调节剂。 GATA1 阳性 AML 的增殖和维持以及改善这些白血病的治疗反应不佳。为了解决我们的假设，我们将： 1. 确定角色 2. 建立 SMS1 作为 GATA1 阳性 AML 细胞中 SMS1 的新靶点针对 GATA1 阳性 AML 的治疗干预。我们的提案旨在将 SMS1 建立为 GATA1+ AML 细胞的新型关键调节因子，并可能提供一种分子信息丰富且急需的新治疗方案，用于用红系或红细胞治疗 AML 巨核细胞富集。