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）儿童患急性髓样白血病（AML）的风险很高。 DS中的AML具有独特的特征：a）通常具有巨核细胞表型（AMKL）； b）DS-AMKL的无事件生存率远高于AMKL的非DS儿童（〜75-100％对<25％）； c）AMKL可能是在大约10％的DS新生儿中发生的瞬时脊髓增生性疾病（TMD），并在约20％的情况下演变为AMKL，而在其他情况下则自发解决。 DS中AML独特病理生物学基础的分子和细胞事件仍有待阐明。小型回顾性研究已经确定了仅在DS TMD和AMKL病例中的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，也可以增强白血病细胞对化学疗法的敏感性。该提案利用了计划在儿童肿瘤学组临床试验中计划的相关生物学研究AAML0431“对AML和MDS 4岁以下的DS儿童的治疗”和AAML0532“治疗DS TMD儿童的治疗”。特定目标1中的研究将确定并比较DS TMD和AML病例中GATA1突变的频率及其与AMKL表型的关系。在此目的中，还将追求与包括JAK3突变（JAK3突变）和MicroRNA表达改变的AMKL发展相关的二级遗传事件的鉴定。在特定的目标2中，微阵列研究将确定预测TMD结果的基因，并描述与从TMD到AMKL的过渡相关的分子事件。在特定的目标3中，研究DS AML病例对治疗的反应的药理和分子测定法，包括使用最小残留疾病（MRD）检测来监测诱导治疗期间的治疗反应，该疗法可用于识别适当的细胞滨剂量。在此目标中，将开发用于靶向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仪MRD测定法获得的比较验证的结果。在这些目标下提出的研究中的成功应导致DS和AML儿童的临床管理改善，并提供有关调节AML中白血病生成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）

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.

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

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.