CSF2 receptor mediated actions in t(8;21) leukemia

CSF2 受体介导的 t(8;21) 白血病作用

• 批准号: 9014529
• 负责人: DONG-ER ZHANG
• 金额: $ 34.49万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-02-13 至 2020-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9014529
• 关键词: AML1-ETO fusion protein; Acute Myelocytic Leukemia; Address; Affect; Age; Alleles; Apoptosis; Blast Phase; CBFA2T1 gene; CSF2RA gene; Cell Cycle Arrest; Cell Line; Cell Proliferation; Cell Survival; Cell model; Cells; Chimeric Proteins; Chromosomal translocation; Chromosomes, Human, Pair 21; Chromosomes, Human, Pair 8; Chromosomes, Human, X; Colony-Stimulating Factor Receptors; Colony-Stimulating Factors; Data; Development; Diagnosis; Ethnic group; Frequencies; Funding; Genes; Geographic Locations; Goals; Health; Hematopoiesis; Hematopoietic; Hematopoietic Neoplasms; Human; IL5 gene; Incidence; Interleukin-3 Receptor; K-562; K562 Cells; Knowledge; Lead; M2 Acute Myeloid Leukemia; Mediating; Molecular; Mus; Myelogenous; Outcome; Pathway interactions; Patients; Play; Production; Proteins; Pseudoautosomal Region; RUNX1 gene; Relapse; Reporting; Resistance; Role; Sex Chromosomes; Signal Pathway; Signal Transduction; Stem cells; Testing; Time; Toxic effect; Transgenic Mice; X Chromosome; Y Chromosome; alternative treatment; autosome; base; bcr-abl Fusion Proteins; chemotherapy; cytokine; effective therapy; in vitro Assay; in vivo; insight; interest; leukemia; leukemic stem cell; leukemogenesis; mouse model; novel; novel strategies; outcome forecast; promoter; receptor; self-renewal; standard of care; stem; t(8; 21)(q22; q22); targeted treatment

 DESCRIPTION (provided by applicant): The overall goal of this proposal is to understand the role of CSF2 and its specific receptor CSF2Rα in the development of t(8;21) leukemia. The 8 and 21 chromosome translocation, t(8;21)(q22;q22), is responsible for the development of 40% of FAB M2 type of acute myeloid leukemia (AML) and is reported in 8-15% of cases of AML, depending on geographic locations and ethnic groups. Age is the most correlated factor for AML. Most AML patients are over 60 years old at the initial diagnosis. However, t(8;21) AML patients are relatively young and most respond to initial chemotherapy well. Therefore, t(8;21) AML is generally considered with favorable prognosis. However, the cumulative incidence of relapse in 5 years is 47%, and the median overall survival time is only 5 years among de novo t(8;21) AML patients. Furthermore, therapy-related t(8;21) AML does not have a favorable outcome. Therefore, it is important to identify new approaches to eliminate t(8;21) leukemia stem cells during the initial induction treatment and to block the survival and proliferation of chemo-resistant leukemia cells. The fusion of ETO gene on chromosome 8 and AML1 gene on chromosome 21 in t(8;21) leads to the expression of the abnormal AML1-ETO protein. Using several transgenic mouse models and available human patient data, we discovered that colony stimulating factor 2 (CSF2) negatively regulates AML1-ETO induced self-renewal of hematopoietic stem/progenitor cells and AML development. Furthermore, expression of the CSF2-specific receptor subunit, CSF2Rα, in t(8;21) AML cells reduces cell proliferation and survival. In this funding application, we will test the hypotheses that selected CSF2 downstream pathways play critical roles in suppression of t(8;21) leukemia and that CSF2Rα may have functions independent of CSF2 signaling in inhibition of t(8;21) leukemia. We propose to perform the following studies to test the hypotheses: in specific aim 1, we will characterize the molecular pathways of CSF2 signaling that mediate inhibition of AML1-ETO induced leukemia; in specific aim 2, we will analyze the effect of CSF2RA expression on t(8;21) leukemogenesis. The proposed studies are based on our accumulated knowledge and recent novel findings involving CSF2 signaling and CSF2Rα in AML1-ETO induced leukemia. Collectively, our proposal will address important unanswered questions in hematopoiesis and leukemogenesis, which aim to provide valuable insight into the treatment of t(8;21) leukemia.