Molecular and Pharmacologic Correletes of Acute Myeloid Leukemia in Down Syndrome

唐氏综合症急性髓系白血病的分子和药理学相关性

基本信息

批准号：
8099603
负责人：
JEFFREY Warren TAUB
金额：
$ 41.17万
依托单位：
WAYNE STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-07-06 至 2014-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8099603
关键词：
4 year old Accounting Acute Megakaryocytic Leukemias Acute Myelocytic Leukemia Address Anthracyclines Applications Grants Ara-C Biological Biological Assay Biology Cardiac Cardiotoxicity Cell Line Cells Child Childhood Leukemia Children&apos s Oncology Group Chromosomes, Human, Pair 21 Clinical Clinical Management Clinical Trials Correlative Study Cytarabine Daunorubicin Detection Detection of Minimal Residual Disease Development Disease-Free Survival Dose Down Syndrome Drug Kinetics Event Frequencies Future GATA1 gene Gene Expression Generations Genes Genetic Genetic Polymorphism JAK3 gene Kinetics Late Effects Lead Link Megakaryocytopoieses Metabolism MicroRNAs Microarray Analysis Modeling Molecular Monitor Mutation Myeloproliferative disease Neoadjuvant Therapy Neonatal Screening Newborn Infant Outcome Patients Pattern Pharmacotherapy Phenotype Process Protein Tyrosine Kinase Regimen Residual Neoplasm Retrospective Studies Risk Role Sampling Somatic Mutation Subgroup Survival Rate Time Toxic effect Transcription factor genes Variant base chemotherapy clinically relevant disorder risk drug sensitivity high risk insight leukemia leukemogenesis novel population based postnatal prenatal response success transient myeloproliferative disorder treatment response

项目摘要

DESCRIPTION (provided by applicant): Down syndrome (DS) children have a high risk of developing acute myeloid leukemia (AML). AML in DS has unique features: a) it typically presents with a megakaryocytic phenotype (AMkL); b) event-free survival rates for DS-AMkL are much higher than non-DS children with AMkL (~75-100% versus <25%); c) AMkL may be preceded by a transient myeloproliferative disorder (TMD) which occurs in approximately 10% of DS newborns and evolves into AMkL in ~20%, while resolving spontaneously in the others. The molecular and cellular events underlying the unique pathobiology of AML in DS remain to be elucidated. Small retrospective studies have identified somatic mutations of the X-linked transcription factor gene, GATA1, exclusively in DS TMD and AMkL cases. Conceivable, GATA1 mutations could contribute to leukemogenesis and also enhance the sensitivity of leukemia cells to chemotherapy. This proposal takes advantage of correlative biological studies planned in the Children's Oncology Group clinical trials AAML0431 "Treatment of DS Children with AML and MDS Under the Age of 4 Years" and AAML0532 "The Treatment of DS Children with TMD". Studies in Specific Aim 1 will determine and compare the types of frequency of GATA1 mutations in DS TMD and AML cases and their relationship to the AMkL phenotype. The identification of secondary genetic events linked to the development of AMkL including JAK3 mutations and altered microRNA expression will also be pursued in this Aim. In Specific Aim 2, microarray studies will identify genes that predict TMD outcome, and to describe the molecular events associated with the transition from TMD to AMkL. In Specific Aim 3, pharmacologic and molecular assays to study the response of DS AML cases to therapy including the use of minimal residual disease (MRD) detection to monitor treatment response during induction therapy, which may be used to identify the appropriate cytarabine dose in clinical trials. Within this aim, a novel molecular assay for MRD detection targeting GATA1 mutations will be developed and the results validated by comparisons with those obtained with the established flow cytometric MRD assay. Success in the studies proposed under these aims should lead to improvements in the clinical management of children with DS and AML, and also provide unique information about the fundamental mechanism that regulate leukemogenesis and drug sensitivity in AML.

描述（由申请人提供）：唐氏综合症（DS）儿童患急性髓系白血病（AML）的风险很高。 DS 中的 AML 具有独特的特征：a) 通常表现为巨核细胞表型 (AMkL)； b) DS-AMkL 的无事件生存率远高于非 DS AMkL 儿童（约 75-100% 对比 <25%）； c) AMkL 之前可能会出现短暂性骨髓增生性疾病 (TMD)，大约 10% 的 DS 新生儿会发生这种疾病，约 20% 的新生儿会演变成 AMkL，而其他新生儿会自行消退。 DS 中 AML 独特病理学背后的分子和细胞事件仍有待阐明。小型回顾性研究仅在 DS TMD 和 AMkL 病例中发现了 X 连锁转录因子基因 GATA1 的体细胞突变。可以想象，GATA1突变可能有助于白血病的发生，并增强白血病细胞对化疗的敏感性。该提案利用了儿童肿瘤学组临床试验AAML0431“4岁以下患有AML和MDS的DS儿童的治疗”和AAML0532“患有TMD的DS儿童的治疗”中计划的相关生物学研究。具体目标 1 中的研究将确定并比较 DS TMD 和 AML 病例中 GATA1 突变频率的类型及其与 AMkL 表型的关系。该目标还将鉴定与 AMkL 发展相关的次要遗传事件，包括 JAK3 突变和 microRNA 表达改变。在具体目标 2 中，微阵列研究将鉴定预测 TMD 结果的基因，并描述与从 TMD 转变为 AMkL 相关的分子事件。在具体目标 3 中，通过药理学和分子检测来研究 DS AML 病例对治疗的反应，包括使用微小残留病 (MRD) 检测来监测诱导治疗期间的治疗反应，这可用于确定临床中适当的阿糖胞苷剂量试验。在此目标下，将开发一种针对 GATA1 突变的 MRD 检测的新型分子测定法，并通过与已建立的流式细胞术 MRD 测定法获得的结果进行比较来验证结果。根据这些目标提出的研究的成功应该会改善 DS 和 AML 儿童的临床管理，并提供有关调节 AML 白血病发生和药物敏感性的基本机制的独特信息。

项目成果

期刊论文数量（9）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Valproic acid synergistically enhances the cytotoxicity of clofarabine in pediatric acute myeloid leukemia cells.

DOI：
10.1002/pbc.24152
发表时间：
2012-12-15
期刊：
PEDIATRIC BLOOD & CANCER
影响因子：
3.2
作者：
Xie, Chengzhi;Edwards, Holly;LoGrasso, Salvatore B.;Buck, Steven A.;Matherly, Larry H.;Taub, Jeffrey W.;Ge, Yubin
通讯作者：
Ge, Yubin

Targeting the wee1 kinase for treatment of pediatric Down syndrome acute myeloid leukemia.

DOI：
10.1002/pbc.25081
发表时间：
2014-10
期刊：
PEDIATRIC BLOOD & CANCER
影响因子：
3.2
作者：
Caldwell, J. Timothy;Edwards, Holly;Buck, Steven A.;Ge, Yubin;Taub, Jeffrey W.
通讯作者：
Taub, Jeffrey W.

Mechanisms of synergistic antileukemic interactions between valproic acid and cytarabine in pediatric acute myeloid leukemia.

DOI：
10.1158/1078-0432.ccr-10-1707
发表时间：
2010-11-15
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
0
作者：
Xie C;Edwards H;Xu X;Zhou H;Buck SA;Stout ML;Yu Q;Rubnitz JE;Matherly LH;Taub JW;Ge Y
通讯作者：
Ge Y

Hsa-mir-125b-2 is highly expressed in childhood ETV6/RUNX1 (TEL/AML1) leukemias and confers survival advantage to growth inhibitory signals independent of p53.