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Mechanism of Therapy in high-risk AML

高危AML的治疗机制

基本信息

批准号：
10176429
负责人：
Mohammad Azam
金额：
$ 48.84万
依托单位：
CINCINNATI CHILDRENS HOSP MED CTR
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-01 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10176429
关键词：
ATAC-seq Acute Myelocytic Leukemia Alleles Apoptotic Binding Biochemical Cells Chemicals Chemotherapy-Oncologic Procedure Chromatin Chronic Myeloid Leukemia Combined Modality Therapy Complex Complex Analysis DNMT3a DUSP1 gene Data Dependence Disease Disease Outcome Dissection Drug resistance Ectopic Expression Enhancers FLT3 gene FLT3 inhibitor FOS gene Family Genes Genetic Genetic Models Genetic Transcription Genomics Goals Hematologic Neoplasms In Vitro Internal Ribosome Entry Site JUNB gene Leukemic Cell Link MLL-AF9 Malignant - descriptor Malignant Neoplasms Mediating Medicine Modeling Molecular Molecular Analysis Mus Mutate Mutation NPM1 gene Nature Normal Cell Oncogenic Pancytopenia Pathogenesis Pathway interactions Patients Pharmaceutical Preparations Pharmacology Pharmacotherapy Phosphotransferases Prognosis Protein Tyrosine Kinase Proteins Publications RUNX1 gene Recurrent disease Regulation Reporter Reporter Genes Resistance Risk Sampling Signal Transduction TP53 gene Testing Therapeutic Transcription Factor AP-1 Treatment Efficacy Treatment Failure Validation Wild Type Mouse Work acute myeloid leukemia cell base cancer cell chemotherapy clinically relevant combinatorial dimer drug sensitivity experimental study high risk humanized mouse in vivo inhibitor/antagonist insight jun Oncogene leukemia leukemic transformation mouse genetics mouse model novel novel therapeutics overexpression prevent refractory cancer response small molecule targeted treatment therapeutic target therapy outcome therapy resistant transcription factor transcriptome sequencing treatment group treatment response treatment strategy tumor tumorigenesis whole genome

项目摘要

Acute myeloid leukemia (AML) is an aggressive hematologic malignancy that, despite being treatable with well- defined chemotherapy regimens, is ultimately fatal in over half of all cases categorized as high-risk AML. Mutations in MLL, FLT3, DNMT3A and P53 are associated with high-risk AML. Even targeted FLT3 anti kinase therapy, which constitutes 30 % of AML, failed to engender durable response in this group of AML. Co-operative oncogenic signaling” was attributed to poor therapeutic outcome, but lacks mechanistic understanding. Based on our recent publication and new preliminary data, we found that co-operative oncogenic signaling converges on c-FOS and DUSP1, which results in an increased apoptotic threshold in cancer cells and confers drug resistance. Thus, genetic or pharmacologic inhibition of c-FOS and DUSP1 sensitizes cancer cells to chemotherapy (Kesarwani, et. al. Nature Medicine 2017). We show greater expression of c-FOS and DUSP1 in high-risk AML patients, but not in low risk-AML patients. Both genetic and chemical inhibition of c-FOS and DUSP1 results in increased drug sensitivity to both TKI and conventional chemotherapeutic drugs in a model of high-risk AML (FLT3ITD+MLLAF9). Thus, we hypothesize that co-operative oncogenic signaling in AML induces the expression of c-FOS and DUSP1 resulting to drug resistance and disease relapse due to elevated apoptotic threshold. In Aim 1, we will determine whether c-FOS and DUSP1 are necessary and sufficient for transformation in a most frequent, aggressive, and fatal AML driven by FLT3ITD+DNMT3Amut+NPM1C and FLT3ITD+P53mut mutations. We will examine the cellular basis of c-FOS and DUSP1 dependency in the high- risk AML mouse models and primary patient samples by genetic deletion and pharmacological inhibition of c- FOS and DUSP1. Next, we propose experiments to understand the mechanistic basis for how co-operative oncogenic signaling via c-FOS and DUSP1 contributes to transformation and treatment failure in AML, with the goal for novel treatment strategies. Based on our preliminary data, we hypothesize that c-FOS and DUSP1 signaling converges upon oncogenically-activated enhancers mediated by specific AP-1 transcriptional complexes. In the presence of c-FOS and DUSP1, AP-1 complexes consist of c-FOS-JUN, which mediate oncogenically-active enhancers, while in the absence of c-FOS and DUSP1, Jun family homodimers (JUN- JUNB, JUNB-JUND, JUN-JUND) predominate which are unable to support the leukemic cell state. In Aim 2, we will molecularly link c-FOS-JUN AP-1 and DUSP1 activity to global enhancer chromatin dynamics. Moreover, we will exploit chromatin-embedded target-gene-reporter alleles to provide a detailed analysis of functionally-relevant downstream genes at a single-cell level in high-risk AML. The proposed work is expected to delineate the necessity of c-FOS and DUSP1 signaling in high-risk AML, as well as to provide deep molecular insight into the mechanisms underlying leukemic transformation and drug resistance. We expect that this information will be informative not only for AML, but also the broad group of treatment resistant tumors.

急性髓性白血病（AML）是一种侵袭性血液恶性肿瘤，尽管可以用良好的药物治疗，在所有归类为高风险AML的病例中，超过一半的病例最终是致命的。 MLL、FLT 3、DNMT 3A和P53突变与高危AML相关。甚至靶向FLT 3抗激酶占AML的30%的治疗未能在该组AML中产生持久的反应。合作致癌信号传导”归因于不良的治疗结果，但缺乏对机制的理解。基于根据我们最近的出版物和新的初步数据，我们发现，合作致癌信号收敛，对c-FOS和DUSP 1的作用，这导致癌细胞凋亡阈值增加，并赋予药物阻力因此，c-FOS和DUSP 1的遗传或药理学抑制使癌细胞对以下物质敏感：化学疗法（Kesarwani，et. Nature Medicine 2017）。我们发现c-FOS和DUSP 1的表达更高，在高风险AML患者中，但在低风险AML患者中没有。基因和化学抑制c-FOS和 DUSP 1导致模型中对TKI和常规化疗药物的药物敏感性增加高危AML（FLT 3 ITD + MLLAF 9）。因此，我们假设AML中的协同致癌信号传导诱导c-FOS和DUSP 1的表达，导致药物抗性和疾病复发，凋亡阈值在目标1中，我们将确定c-FOS和DUSP 1是否是必要和充分的，在FLT 3 ITD + DNMT 3Amut + NPM 1C驱动的最常见、侵袭性和致死性AML中发生转化， FLT 3 ITD + P53突变。我们将研究c-FOS和DUSP 1依赖性的细胞基础，风险AML小鼠模型和主要患者样品通过基因缺失和药理学抑制c- FOS和DUSP 1。接下来，我们提出实验来理解合作的机制基础，通过c-FOS和DUSP 1的致癌信号传导有助于AML的转化和治疗失败，新的治疗策略的目标。基于我们的初步数据，我们假设c-FOS和DUSP 1 信号传导会聚在由特异性AP-1转录因子介导的致癌激活增强子上配合物在存在c-FOS和DUSP 1的情况下，AP-1复合物由c-FOS-JUN组成，其介导致癌活性增强子，而在不存在c-FOS和DUSP 1的情况下，Jun家族同源二聚体（JUN-1） JUNB、JUNB-JUND、JUN-JUND）占优势，其不能支持白血病细胞状态。在目标2中，我们将c-FOS-JUN AP-1和DUSP 1活性与全局增强子染色质动力学分子联系起来。此外，我们将利用染色质嵌入的靶基因报告等位基因提供详细的分析，功能相关的下游基因在高风险AML的单细胞水平。拟议的工作预计阐明c-FOS和DUSP 1信号在高危AML中的必要性，并提供深入的对白血病转化和耐药性机制的分子洞察。我们预计该信息不仅对AML，而且对广泛的治疗抗性肿瘤组都是有用的。