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.

项目摘要： 被诊断患有急性髓性白血病（AML）的儿童继续效果不佳，率很差 该方法复发40％。复发性疾病特别抵抗常规疗法。 不幸的是，在复发小儿​​AML中常见的分子改变的定义很差。 最近，我们的小组报道了136名复发AML和AML和 在近10％ 患有AML的孩子。我们进一步证明了UBTF-Tandem重复（UBTF-TD）AML是 也存在于4％的儿童诊断中，但在成年人中很少见，并且通常发生在FLT3-ITD和 WT1突变以及正常的核型细胞遗传学或三体性8。重要的是，我们证明了 UBTF-TD AML的儿童的总生存率较低，残留疾病的率很高 诱导化疗后。我们的初步功能研究已经证实了UBTF-TD表达 足以驱动原代人造血细胞的增殖和自我更新，并且UBTF-TD 蛋白质保持野生型UBTF的规范相互作用，但也与新蛋白质/网络相互作用 在白血病开发中很重要，例如KMT2A和XPO1。这些基因组，功能和 临床发现表明，UBTF-TD AML代表了儿科AML的新分子类别和 建立一个强大的科学前提来研究UBTF串联重复的分子影响 原代造血细胞。我们假设UBTF-TD在新的启动病变中代表 特定转录网络的表达，尤其是HOXB程序，通过与新的交互 基因组以及与独特的合作突变和相互作用蛋白质的合作。我们将测试 我们使用人和小鼠中遗传工具组合的以下特定目的的假设 造血细胞。具体目标1：破译白血病中UBTF-TD的分子机制； 具体目标2：剖析UBTF-TD和共体突变对使用中的白血病发生的贡献 体内模型；特定目的3。建立UBTF域和相互作用蛋白质对UBTF-的贡献 TD介导的转换。拟议的研究不仅会阐明转录和表观遗传学 UBTF-TD表达在原发性造血细胞（包括患者样本）中的影响，但也将 为这种高风险小儿AML和 评估潜在的漏洞。这些提出的研究成功完成了 模型系统最终将用于开发针对UBTF-TD AML的治疗方法 重要的是要改善这些白血病儿童的长期结局。