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