UBTF Tandem Duplications in Pediatric Acute Myeloid Leukemia

儿童急性髓性白血病中的 UBTF 串联重复

• 批准号: 10801150
• 负责人: Jeffery M Klco
• 金额: $ 41.63万
• 依托单位: ST. JUDE CHILDREN'S RESEARCH HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-22 至 2028-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10801150
• 关键词: ATAC-seq; Acute Myelocytic Leukemia; Adult; Binding; Biogenesis; Biological Models; C57BL/6 Mouse; CD34 gene; CRISPR/Cas technology; Categories; Cell model; Cells; Child; Childhood Acute Myeloid Leukemia; Childhood Leukemia; Chromatin; Clinical; Collaborations; Cytogenetics; Data; Development; Diagnosis; Engraftment; Epigenetic Process; Event; Exons; FLT3 gene; Fusion Oncogene Proteins; Future; Gene Expression Profile; Gene Expression Profiling; Gene Frequency; Genes; Genetic; Genetic Transcription; Genome; Genomics; Goals; Growth; Hematopoiesis; Hematopoietic; Heterozygote; Human; Immunodeficient Mouse; Inferior; Karyotype; Lead; Lesion; MLL gene; Maintenance; Mediating; Modeling; Molecular; Mus; Mutation; Nucleolar Proteins; Outcome; Patients; Penetrance; Phenotype; Proliferating; Proteins; Recurrence; Recurrent disease; Relapse; Reporting; Residual Neoplasm; Resistance; Ribosomes; Role; Sampling; Series; Testing; Therapeutic; Transplantation; Trisomy 8; Umbilical Cord Blood; WT1 gene; chemotherapy; conventional therapy; genetic variant; high risk; human model; improved; in silico; in vivo Model; insight; knowledge of results; leukemia; leukemic transformation; leukemogenesis; loss of function mutation; molecular subtypes; mouse model; multiple omics; novel; patient derived xenograft model; programs; self-renewal; small molecular inhibitor; therapeutic target; tool; transcription factor

PROJECT SUMMARY: Children diagnosed with acute myeloid leukemia (AML) continue to have an overall poor outcome with rates of relapse that approach 40%. Relapsed disease is particularly resistant to conventional therapy. Unfortunately, the molecular alterations that are common in relapsed pediatric AML have been poorly defined. Recently our group reported on the spectrum of genetic changes in 136 children with relapsed AML and identified tandem duplications of exon 13 of UBTF (upstream binding transcription factor) in nearly 10% of children with relapsed AML. We further demonstrated that UBTF-tandem duplication (UBTF-TD) AMLs are also present in 4% of children at diagnosis, yet are rare in adults, and commonly occur with FLT3-ITD and WT1 mutations along with either normal karyotype cytogenetics or trisomy 8. Importantly, we demonstrated that children with UBTF-TD AML have an inferior overall survival and high rates of minimal residual disease after induction chemotherapy. Our preliminary functional studies have confirmed that UBTF-TD expression is sufficient to drive proliferation and self-renewal of primary human hematopoietic cells and that UBTF-TD proteins maintain canonical interactions of wild-type UBTF, but also interact with new proteins/networks important in leukemia development, such as KMT2A and XPO1. Collectively these genomic, functional and clinical findings suggest that UBTF-TD AMLs represents a new molecular category of pediatric AML and establishes a strong scientific premise to investigate the molecular impact of UBTF tandem duplications in primary hematopoietic cells. We hypothesize that UBTF-TD represents in new initiating lesion that drives the expression of specific transcriptional networks, in particular the HOXB program, through new interactions with the genome and from collaboration with unique cooperating mutations and interacting proteins. We will test our hypothesis with the following specific aims using a combination of genetic tools in human and mouse hematopoietic cells. Specific Aim 1: Decipher the molecular mechanisms of UBTF-TD in leukemogenesis; Specific Aim 2: Dissect the contribution of UBTF-TD and co-occurring mutations to leukemogenesis using in vivo models; Specific Aim 3. Establish the contribution of UBTF domains and interacting proteins to UBTF- TD mediated transformation. Not only will the proposed studies elucidate the transcriptional and epigenetic impact of UBTF-TD expression in primary hematopoietic cells, including patient samples, but they will also establish multiple mouse and human model systems for this new subtype of high-risk pediatric AML and evaluate potential vulnerabilities. The successful completion of these proposed studies, and the resulting model systems, will ultimately be used to develop therapeutic approaches to target UBTF-TD AMLs and most importantly to improve the long-term outcome of children with these leukemias.

项目概要： 诊断为急性髓细胞白血病（AML）的儿童总体预后不良， 复发率接近40%复发性疾病对常规治疗特别有抵抗力。 不幸的是，在复发的儿童AML中常见的分子改变一直定义不清。 最近，我们的小组报告了136例复发性AML儿童的遗传变化谱， 在近10%的人中发现了UBTF（上游结合转录因子）外显子13的串联重复， 儿童AML复发。我们进一步证明了UBTF-串联重复（UBTF-TD）AML是 在诊断时也存在于4%的儿童中，但在成人中罕见，通常发生于FLT 3-ITD， WT 1突变沿着正常核型细胞遗传学或8三体。重要的是，我们证明了 UBTF-TD AML儿童的总体生存率较低，微小残留病的发生率较高， 诱导化疗后。我们的初步功能研究证实，UBTF-TD表达 足以驱动原代人造血细胞和UBTF-TD增殖和自我更新 蛋白质保持野生型UBTF的典型相互作用，但也与新的蛋白质/网络相互作用 在白血病发展中起重要作用，如KMT 2A和XPO 1。这些基因组、功能和 临床结果表明，UBTF-TD AML代表了一种新的儿童AML分子类别， 建立了一个强有力的科学前提，以调查分子的影响，UBTF串联重复， 初级造血细胞我们假设UBTF-TD代表新的起始病变， 表达特定的转录网络，特别是HOXB程序，通过新的相互作用， 基因组和独特的合作突变和相互作用的蛋白质的合作。我们将测试 我们的假设具有以下特定目的，使用人类和小鼠的遗传工具组合 造血细胞具体目标1：阐明UBTF-TD在白血病发生中的分子机制; 具体目标2：使用基因芯片分析UBTF-TD和共现突变对白血病发生的贡献。 体内模型;具体目标3.确定UBTF结构域和相互作用蛋白对UBTF的贡献- TD介导的转化。这项研究不仅将阐明基因的转录和表观遗传 UBTF-TD表达在原代造血细胞中的影响，包括患者样品，但它们也将 为这种新的高危儿科AML亚型建立多种小鼠和人类模型系统， 评估潜在的漏洞。成功完成这些拟议的研究， 模型系统，最终将用于开发靶向UBTF-TD AML的治疗方法， 重要的是改善这些白血病儿童的长期预后。