Genetic Dissection of Acute Myeloid Leukemia.

急性髓系白血病的基因剖析。

基本信息

批准号：
9025470
负责人：
Iannis Aifantis
金额：
$ 35.6万
依托单位：
NEW YORK UNIVERSITY SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-01-01 至 2018-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9025470
关键词：
Acetylation Acute Myelocytic Leukemia Acute leukemia Address Adult Affect Aftercare Agonist Animal Disease Models Animal Model Antibodies Apoptotic Biochemical Biological Blood Cell Death Cell Line Cells Cessation of life ChIP-seq Chromatin Chronic Myelomonocytic Leukemia Coupled DNA Methylation Data Development Diagnosis Disease Dissection Dysmyelopoietic Syndromes Epigenetic Process Event Family Frequencies Future Genes Genetic Genomic approach Genomics Growth Health Histone H3 Human In Vitro JAK2 gene KRAS2 gene Lead Lesion Letters Ligands Massive Parallel Sequencing Methylation Molecular Monocytic leukemia Mus Mutation Myelogenous Myeloid Leukemia Myeloproliferative disease Notch Signaling Pathway Pathway interactions Patients Pattern Peptide antibodies Peptides Publishing Regulation Relapse Reporting Role Signal Transduction Solid Stem cell transplant Survival Rate System Testing Therapeutic Tumor Suppressor Proteins United States Work base chemotherapy clinically significant extracellular genetic approach histone methylation human data human disease in vivo innovation leukemia leukemogenesis methylome mouse model notch protein novel novel therapeutic intervention operation receptor expression relapse patients targeted treatment tool tumor whole genome

项目摘要

DESCRIPTION (provided by applicant): AML is a devastating blood tumor, the most common type of leukemia in adults, a disease that continues to have the lowest survival rate within leukemia. Nearly 45,000 people are diagnosed each year in the US, and the current 5-year survival frequency is only 24% with an almost 50% relapse rate after treatment. AML is a part of a wider family of myeloid neoplasms that include diverse but related diseases like myelodysplastic syndromes (MDS), myeloproliferative neoplasms (MPN) and chronic myelomonocytic leukemia (CMML), a disease that frequently develops into AML. Currently, there are no targeted therapies for most of these diseases, including AML, making the study of the molecular mechanisms of their induction and progression of great significance. We have recently identified novel somatically acquired mutations inactivating the Notch signaling pathway in patients with CMML. Interestingly, these Notch mutations do not act in isolation but they co-occur with additional genomic "hits", including mutations on the TET2, ASXL1, KRAS and JAK2 genes. Our published and preliminary data presented here demonstrate that: a) The Notch pathway is "switched-off" in myelo-monocytic leukemias, including AML, b) Inhibition of the pathway is achieved both by inactivating mutations and epigenetic silencing, c) Re-activation of the pathway can inhibit the growth of mouse CMML in vivo and human AML in vitro. In this application we: a) Assess the biological effects of Notch pathway re- activation in AML, b) Identify the molecular and epigenetic mode of pathway inhibition in human AML and c) Study co-operation of Notch pathway mutations with additional genomic lesions and their effect in AML initiation and progression. We strongly believe that these studies can lead to future targeted therapies of AML and related myeloid neoplasms, as re-activation of the Notch pathway can be achieved using both peptide and antibody agonist approaches.

描述（由申请人提供）：AML是一种毁灭性的血液肿瘤，是成年人中最常见的白血病类型，这种疾病在白血病中的生存率仍然最低。在美国，每年诊断出近45,000人，当前的5年生存频率仅为24％，治疗后近50％的复发率。 AML是更广泛的髓样肿瘤系列的一部分，其中包括多种但相关的疾病，例如髓异增生综合征（MDS），脊髓增生性肿瘤（MPN）和慢性骨髓细胞细胞性白血病（CMML），这种疾病经常发展为AML。当前，包括AML在内的大多数疾病都没有针对性的疗法，可以研究其诱导的分子机制和具有重要意义的进展。我们最近确定了新型的体外获得突变，使CMML患者的Notch信号通路失活。有趣的是，这些缺口突变不是分离起来的，而是与其他基因组“命中”共发生，包括TET2，ASXL1，KRAS和JAK2基因上的突变。 Our published and preliminary data presented here demonstrate that: a) The Notch pathway is "switched-off" in myelo-monocytic leukemias, including AML, b) Inhibition of the pathway is achieved both by inactivating mutations and epigenetic silencing, c) Re-activation of the pathway can inhibit the growth of mouse CMML in vivo and human AML in vitro.在此应用中，我们：a）评估AML中Notch途径重新激活的生物学效应，b）确定人AML和c）在人AML和c中识别途径抑制的分子和表观遗传模式，研究Notch途径突变的合作与其他基因组病变及其在AML启动和进展中的作用。我们坚信，这些研究可以导致未来的AML和相关髓样肿瘤的靶向疗法，因为可以使用肽和抗体激动剂方法来实现Notch途径的重新激活。