Therapeutic Strategies for Anemia in 3q26 Rearranged Leukemia

3q26重排白血病贫血的治疗策略

• 批准号: 9754589
• 负责人: Edward Ayoub
• 金额: $ 0.28万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-01 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9754589
• 关键词: 3q26; ATAC-seq; Acute Myelocytic Leukemia; Address; Alleles; Anemia; Attenuated; Binding; Binding Proteins; Binding Sites; Blood Cells; Bone Marrow; Bone Marrow Transplantation; CRISPR library; Cells; ChIP-seq; Chromatin; Chromatin Remodeling Factor; Chromosomal Rearrangement; Clinical; Clustered Regularly Interspaced Short Palindromic Repeats; Collaborations; DNA Binding; Data; Diagnosis; EVI1 gene; Elements; Enhancers; Erythroblasts; Erythroid; Erythroid Cells; Erythropoiesis; Erythropoietin; Fellowship; GATA1 gene; Genes; Genetic Screening; Genome; Genomics; Goals; Grant; Growth; Hematopoietic Neoplasms; Hematopoietic stem cells; Knock-out; Lead; Lymphopoiesis; Mediating; Modeling; Molecular; Mus; Myelogenous; Myeloid Progenitor Cells; Myelopoiesis; Oncogenes; Patients; Pattern; Publishing; Purines; Relapse; Reporting; Research; Role; Severities; Site; Survival Rate; System; Techniques; Testing; Tetracyclines; Therapeutic; Training; Translating; United States National Institutes of Health; Up-Regulation; Upstream Enhancer; Viral; cancer statistics; cancer type; clinical application; erythroid differentiation; experimental study; hematopoietic differentiation; improved; in vitro Model; in vivo; in vivo Model; insight; interest; knock-down; lambda Spi-1; leukemia; leukemogenesis; mouse model; new therapeutic target; novel therapeutic intervention; overexpression; progenitor; recruit; screening; small hairpin RNA; therapeutic target; transcription factor

Project Summary/ Abstract According to the most recent NIH Cancer Statistics Review, leukemia, a cancer of blood cells, is the ninth most common type of cancer. Acute myeloid leukemia (AML) is an aggressive form of leukemia with high lethality (~75% of patients die 5 years after being diagnosed) characterized by anemia, and excessive proliferation of abnormal myeloid progenitor cells in the bone marrow (BM). Rearrangements of the chromosomal band 3q26 portend further reduction in survival, and lead to the overexpression of the oncogene Ecotropic Viral Integration Site 1 (EVI1). The severity of 3q26 rearranged AML, the lack of in-depth understanding of the role of EVI1 in leukemia, and the inadequate therapeutic strategies interested our lab and others to investigate EVI1 associated leukemogenesis. While previous groups used transplantation of BM virally transduced to overexpress EVI1, we are the first lab to recapitulate the effects of the 3q26 rearrangements in the mouse by establishing an inducible EVI1-overexpression model, which has provided us with new insights into the mechanisms by which EVI1 induces leukemia. We concluded using our in vivo and in vitro models that EVI1 causes myeloid expansion and blocks both erythropoiesis and lymphopoiesis. As an insight to the molecular mechanism, we previously documented that EVI1 binds to GACAAGATA, which overlaps with the binding site of the master regulator of erythropoiesis GATA-1. Additionally, our data indicate that EVI1 upregulates a previously published GATA-1 blocker, PU.1, and we showed that EVI1 binds to an enhancer upstream of PU.1 encoding gene (Spi-1). Thus, we hypothesize that EVI1 blocks erythroid differentiation by two mechanisms: 1) directly competing with GATA- 1 for key genomic binding sites harboring EVI1/GATA-1 overlap motifs and 2)!binding to Spi-1 enhancer and upregulating PU.1, which suppresses GATA1 function. We will investigate both hypothesized mechanisms using cutting edge techniques including ChIP-seq, ATAC-seq, and CRISPR under the training of my sponsor and collaborator. In order to translate the proposed mechanistic insights into clinical settings and therapeutic strategies, we will perform CRISPR library screening using an in vivo model to identify genes that reverse erythropoiesis blockage associated with EVI1-overexpression. In summary, this fellowship will focus on investigating erythropoiesis blockage and resulting anemia that might explain the increased lethality associated with 3q26 rearranged leukemia, and It will unveil new therapeutic strategies that reverse the leukemia-associated anemia.

项目摘要/摘要 根据最新的NIH癌症统计评论，血细胞癌是第九个血清癌。 常见的癌症类型。急性髓样白血病（AML）是一种侵略性的白血病，具有高致死性 （诊断出5年后，约有75％的患者死亡），其特征是贫血，过度的增殖 骨髓（BM）中的髓样祖细胞异常。染色体带3Q26的重排 预示生存的进一步降低，并导致癌基因生态病毒整合的过表达 站点1（EVI1）。 3q26重新排列的AML的严重程度缺乏对EVI1在的作用的深入了解 白血病，以及我们实验室和其他人对EVI1相关的治疗策略不足 白血病。虽然先前的组使用了对过表达EVI1的BM的移植，但我们 是第一个通过建立可诱导的实验室来概括小鼠中3Q26重排的影响的实验室 EVI1-Over表达模型，它为我们提供了对EVI1的机制的新见解 诱发白血病。我们使用我们的体内和体外模型得出结论，这些模型会导致髓样膨胀和 阻止红细胞生成和淋巴管。作为对分子机制的见解，我们以前 记录EVI1与Gacaagata结合，该结合与主调节器的结合位点重叠 红细胞生成GATA-1。此外，我们的数据表明EVI1上调了先前发布的GATA-1 Blocker，PU.1，我们表明EVI1与PU.1编码基因（SPI-1）上游的增强子结合。因此， 我们假设EVI1通过两种机制阻止了红细胞分化：1）直接与GATA-竞争 1对于具有EVI1/GATA-1重叠基序的关键基因组结合位点，2）！ 上调PU.1，抑制GATA1函数。我们将使用使用的两个假设机制 在我的赞助商和 合作者。为了将提出的机械见解转化为临床环境和治疗 策略，我们将使用体内模型进行CRISPR库筛选，以识别反向的基因 与EVI1-ERCERDESSION相关的促红细胞阻塞。 总而言之，该奖学金将着重于调查红细胞动物的阻塞和导致的贫血，可能 解释与3q26重排的白血病相关的杀伤力增加，它将推出新的治疗性 扭转白血病相关性贫血的策略。