Mechanism of Therapy in high-risk AML

高危AML的治疗机制

• 批准号: 10657371
• 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
• 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/10657371
• 关键词: ATAC-seq; Acute Myelocytic Leukemia; Alleles; Apoptotic; Binding; Biochemical; Bone marrow failure; Categories; 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; Pharmacotherapy; Phosphotransferases; Prognosis; Protein Tyrosine Kinase; Proteins; Publications; RUNX1 gene; Recurrent disease; Regulation; Reporter; Reporter Genes; Resistance; Resistance development; 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; 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; pharmacologic; 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

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.

急性髓样白血病（AML）是一种侵略性的血液学恶性肿瘤 定义的化学疗法方案最终在所有归类为高风险AML的情况下最终致命。 MLL，FLT3，DNMT3A和P53中的突变与高风险AML有关。甚至靶向的FLT3抗激酶 占AML的30％的治疗未能在这组AML中产生持久的反应。合作 致癌信号传导归因于治疗结果差，但缺乏机械理解。 在我们最近的出版物和新的初步数据中，我们发现合作的致癌信号收敛 关于C-FOS和DUSP1，这导致癌细胞中凋亡阈值增加并承认药物 反抗。那是C-FOS和DUSP1的遗传或药物抑制作用 化学疗法（Kesarwani，等人自然医学2017）。我们显示了C-FOS和DUSP1的更大表达 在高风险AML患者中，但在低风险AML患者中没有。遗传和化学抑制c-fos和 DUSP1在模型中导致对TKI和常规化学治疗药物的药物敏感性提高 高风险AML（FLT3ITD+MLLAF9）。这，我们假设AML中的合作致癌信号传导 诱导C-FOS和DUSP1的表达，导致耐药性和疾病的缓解，原因升高 凋亡阈值。在AIM 1中，我们将确定C-FOS和DUSP1是否需要 由FLT3ITD+DNMT3AMUT+NPM1C驱动的最频繁，侵略性和致命的AML转换 FLT3ITD+P53MUT突变。我们将研究高 - c-fos和dusp1依赖性的细胞基础 通过遗传缺失和c-的药物抑制，将AML小鼠模型和原发性患者样品风险风险 FOS和DUSP1。接下来，我们提出实验，以了解如何合作的机械基础 通过C-FOS和DUSP1致癌信号传导有助于AML中的转化和治疗失败，并有 新颖治疗策略的目标。根据我们的初步数据，我们假设C-Fos和Dusp1 信号传导会在特定AP-1转录介导的肿瘤激活增强子上收敛 复合物。在存在C-FOS和DUSP1的情况下，AP-1复合物由C-FOS-JUN组成，该复合物介导 致力激活的增强子，而在没有C-Fos和Dusp1的情况下，Jun家族同型二聚体（Jun- Junb，Junb-Jund，Jun-jund）占无法支持白血病细胞状态的占主导地位。在AIM 2中， 我们将分子将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，我们将利用与染色质的靶标为基因培养基等位基因相同，以详细分析 在高风险AML中，在功能上与功能相关的下游基因。预计拟议的工作 描绘高危AML中C-Fos和Dusp1信号的必要性，并提供深处 分子洞察白血病转化和耐药性的机制。我们期望这一点 这些信息不仅对AML，而且对广泛的耐药性肿瘤都有信息。

项目成果

Rational polypharmacological targeting of FLT3, JAK2, ABL, and ERK1 suppresses the adaptive resistance to FLT3 inhibitors in AML.

• DOI: 10.1182/bloodadvances.2022007486
• 发表时间: 2023-04-25
• 期刊: BLOOD ADVANCES
• 影响因子: 7.5
• 作者: Azhar, Mohammad;Kincaid, Zachary;Kesarwani, Meenu;Menke, Jacob;Schwieterman, Joshua;Ansari, Sekhu;Reaves, Angela;Ahmed, Arhama;Shehzad, Rammsha;Khan, Areeba;Syed, Nuha;Amir, Noor;Wunderlich, Mark;Latif, Tahir;Seibel, William;Azam, Mohammad
• 通讯作者: Azam, Mohammad

Momelotinib is a highly potent inhibitor of FLT3-mutant AML.

• DOI: 10.1182/bloodadvances.2021004611
• 发表时间: 2022-02-22
• 期刊: Blood advances
• 影响因子: 7.5
• 作者: Azhar M;Kincaid Z;Kesarwani M;Ahmed A;Wunderlich M;Latif T;Starczynowski D;Azam M
• 通讯作者: Azam M