Molecular Pathogenesis of AF10-Rearranged Leukemias

AF10 重排白血病的分子发病机制

• 批准号: 10609055
• 负责人: Aniruddha J. Deshpande
• 金额: $ 44.16万
• 依托单位: SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-12 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10609055
• 关键词: Acute Myelocytic Leukemia; Acute T Cell Leukemia; Address; Adult; Antiparasitic Agents; Biochemical; Bone Marrow; CRISPR screen; Cancer Etiology; Cell Line; Cells; Chemoresistance; Child; Childhood; Childhood Acute Myeloid Leukemia; Childhood Leukemia; Chimeric Proteins; Clinical; Clinical Trials; Combined Modality Therapy; Custom; Cytokine Signaling; Data; Data Analyses; Dependence; Disease; Event; Failure; Functional disorder; Fusion Oncogene Proteins; Gene Activation; Gene Expression; Gene Fusion; Gene Rearrangement; Genes; Genetic; Genetic Transcription; Genomics; Growth Factor; Hematopoietic; Homeobox Genes; Human; Hyperactivity; Impairment; In Vitro; Incidence; Inflammatory; JAK1 gene; Janus kinase; Libraries; Link; Malignant Childhood Neoplasm; Mediating; Methodology; Methods; Modeling; Molecular; Mus; Mutation; Oncoproteins; Outcome; Pathogenesis; Pathway interactions; Patients; Pediatric cohort; Pharmaceutical Preparations; Pre-Clinical Model; Prevalence; Process; Proteomics; Recurrence; Recurrent disease; Refractory; Relapse; Resistance; Role; STAT3 gene; Sampling; Series; Signal Transduction; Testing; Tetracyclines; Therapeutic; Toxic effect; Transcriptional Activation; Xenograft procedure; acute lymphoblastic leukemia cell; acute myeloid leukemia cell; adult leukemia; atovaquone; biobank; cancer cell; cancer cell differentiation; clinically relevant; clinically significant; cohort; cytokine; effective therapy; efficacious treatment; efficacy testing; epigenomics; functional genomics; high risk population; human model; in vivo; inhibitor; leukemia; leukemia treatment; leukemogenesis; mortality; mouse model; new therapeutic target; novel; patient derived xenograft model; pharmacologic; preclinical study; prognostic; self-renewal; side effect; stem cell self renewal; survival outcome; targeted treatment; transcription factor; transcriptomics; treatment response; treatment strategy; tumorigenesis

PROJECT SUMMARY There has been considerable progress in the last few years in the characterization of molecular alterations in childhood cancer. Many defining genomic abnormalities as well as transcriptional and signaling networks involved in specific sub-types of pediatric cancers have been identified. However, despite these impressive advances, safe and effective therapies for most pediatric cancers are lacking. Leukemias are the leading cause of cancer-linked mortality in children and for many pediatric leukemias, therapies that can selectively eliminate cancer cells with few undesirable side effects have been elusive. Therefore, there is an urgent clinically unmet need to develop non-toxic and targeted therapies for pediatric leukemia. Our proposal is focused on leukemias with rearrangements of the AF10 gene. These rearrangements are observed in acute myeloid leukemia (AML), T-cell acute lymphoblastic leukemia (T-ALL) and other sub-types of leukemia in children and adults. AF10-rearranged (AF10-R) leukemias can be considered prototypical models of pediatric cancers in which chimeric fusion oncoproteins or altered transcription factors drive extensive self- renewal and impaired differentiation of cancer cells. Our recent analysis of data from over 1,000 pediatric AML patients demonstrates that AF10 gene fusions are much more common than generally appreciated (representing 6.5% of pediatric AML) and constitute one of the highest risk-groups in terms of resistance to primary therapies and relapse rates. Our detailed mechanistic studies demonstrate that the AF10 fusion protein CALM-AF10 activates a number of pathways linked to stem cell self-renewal and inflammatory signaling, many of which are independently associated with poor outcomes in AML. In this proposal, we will use a series of orthogonal methodologies, including proteomic, genomic, epigenomic and detailed mechanistic studies in both human and mouse AML models, to determine how the CALM-AF10 fusion protein causes leukemogenesis. The successful execution of the proposed aims will advance our efforts towards finding newer targeted therapies for AF10-R AML with fewer unwanted toxicities. Results from our studies also have the potential to significantly influence treatment strategies in several other sub-types of pediatric leukemias driven by related mechanisms.

项目概要 过去几年，在分子改变的表征方面取得了相当大的进展。 儿童癌症。许多定义基因组异常以及转录和信号网络 已确定涉及儿科癌症的特定亚型。然而，尽管有这些令人印象深刻的 尽管取得了进展，但大多数儿科癌症仍缺乏安全有效的治疗方法。白血病是主要原因 儿童癌症相关死亡率和许多儿童白血病的治疗方法可以选择性地消除 几乎没有不良副作用的癌细胞一直难以捉摸。因此，临床上存在一个亟待解决的问题 需要开发针对儿童白血病的无毒靶向疗法。 我们的提案主要针对 AF10 基因重排的白血病。这些重新安排是 在急性髓系白血病 (AML)、T 细胞急性淋巴细胞白血病 (T-ALL) 和其他亚型中观察到 儿童和成人白血病。 AF10 重排 (AF10-R) 白血病可被视为原型模型 嵌合融合癌蛋白或改变的转录因子驱动广泛的自体癌症 癌细胞的更新和分化受损。我们最近对 1,000 多个儿科 AML 的数据进行了分析 患者证明 AF10 基因融合比普遍认为的更为常见（代表 儿童 AML 的 6.5%），构成对主要疗法耐药性最高的风险群体之一 和复发率。我们详细的机制研究表明 AF10 融合蛋白 CALM-AF10 激活许多与干细胞自我更新和炎症信号传导相关的途径，其中许多是 与 AML 不良结局独立相关。在这个提案中，我们将使用一系列正交的 方法学，包括人类和人类的蛋白质组学、基因组学、表观基因组学和详细机制研究 小鼠 AML 模型，以确定 CALM-AF10 融合蛋白如何导致白血病发生。 拟议目标的成功执行将推动我们寻找更新的靶向疗法的努力 用于 AF10-R AML，不良毒性较少。我们的研究结果也有可能显着 影响由相关机制驱动的其他几种儿童白血病亚型的治疗策略。