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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：
10442379
负责人：
Mohammad Azam
金额：
$ 47.86万
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/10442379
关键词：
ATAC-seq Acute Myelocytic Leukemia Alleles Apoptotic Binding Biochemical Bone marrow failure 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 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 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.

急性髓系白血病 (AML) 是一种侵袭性血液恶性肿瘤，尽管可以通过良好的方法治疗，但明确的化疗方案在所有被归类为高危 AML 的病例中，有一半以上最终是致命的。 MLL、FLT3、DNMT3A 和 P53 突变与高危 AML 相关。甚至靶向 FLT3 抗激酶占 AML 30% 的治疗未能在这组 AML 中产生持久的反应。合作社致癌信号”被归因于治疗结果不佳，但缺乏机制理解。基于根据我们最近发表的文章和新的初步数据，我们发现协同致癌信号汇聚作用于 c-FOS 和 DUSP1，导致癌细胞凋亡阈值增加并赋予药物反抗。因此，c-FOS 和 DUSP1 的遗传或药理学抑制使癌细胞对化疗（Kesarwani 等人，Nature Medicine 2017）。我们展示了 c-FOS 和 DUSP1 的更高表达在高风险 AML 患者中，但在低风险 AML 患者中则不然。 c-FOS 的遗传和化学抑制 DUSP1 导致模型中对 TKI 和常规化疗药物的药物敏感性增加高风险 AML (FLT3ITD+MLLAF9)。因此，我们假设 AML 中的协同致癌信号传导诱导c-FOS和DUSP1的表达，导致耐药性和疾病复发，因为c-FOS和DUSP1升高凋亡阈值。在目标 1 中，我们将确定 c-FOS 和 DUSP1 是否是必要且充分的由 FLT3ITD+DNMT3Amut+NPM1C 驱动的最常见、侵袭性和致命性 AML 的转化 FLT3ITD+P53mut 突变。我们将研究 c-FOS 和 DUSP1 依赖性的细胞基础风险 AML 小鼠模型和主要患者样本通过基因删除和药物抑制 c- FOS 和 DUSP1。接下来，我们提出实验来了解合作的机制基础通过 c-FOS 和 DUSP1 的致癌信号传导导致 AML 的转化和治疗失败，新治疗策略的目标。根据我们的初步数据，我们假设 c-FOS 和 DUSP1 信号传导汇聚到由特定 AP-1 转录介导的致癌激活增强子上复合物。在 c-FOS 和 DUSP1 存在的情况下，AP-1 复合物由 c-FOS-JUN 组成，介导致癌活性增强子，而在没有 c-FOS 和 DUSP1 的情况下，Jun 家族同二聚体（JUN- JUNB、JUNB-JUND、JUN-JUND）占主导地位，无法支持白血病细胞状态。在目标 2 中，我们将在分子上将 c-FOS-JUN AP-1 和 DUSP1 活性与全局增强子染色质动力学联系起来。此外，我们将利用染色质嵌入的目标基因报告等位基因来提供详细的分析高风险 AML 中单细胞水平的功能相关下游基因。预计拟议工作描述高风险 AML 中 c-FOS 和 DUSP1 信号传导的必要性，并提供深入的研究对白血病转化和耐药性机制的分子洞察。我们期望这些信息不仅对 AML 有用，而且对广泛的治疗耐药性肿瘤也有用。