Mechanisms of differentiation blockade in CSF3R-mutant AML

CSF3R 突变 AML 分化阻断机制

• 批准号: 10551215
• 负责人: Julia E Maxson
• 金额: $ 37.19万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-02-05 至 2026-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10551215
• 关键词: Acute Myelocytic Leukemia; Adult Acute Myeloblastic Leukemia; Alleles; Binding; Binding Proteins; Biogenesis; Biological Assay; Biology; Blood; Bone Marrow; Cell Line; Childhood; Collaborations; Complex; Core-Binding Factor; Cytokine Receptors; Data; Development; Disease; Down-Regulation; Enhancers; Epigenetic Process; Equilibrium; Event; Evolution; Functional disorder; Future; Genes; Genetic; Genetic Transcription; Goals; Granulocyte Colony-Stimulating Factor Receptors; Hematologic Neoplasms; Hematopoietic; Hematopoietic Neoplasms; Impairment; Malignant Neoplasms; Mediating; Modeling; Molecular; Mutation; Myelogenous; Myeloid Cells; Myeloid Leukemia; NFIX gene; Oncogenes; Other Genetics; Outcome; Patients; Phenotype; Physiological; Production; Prognosis; Proliferating; RUNX1 gene; Recurrent disease; Relapse; Repression; Role; STAT protein; STAT3 gene; Signal Transduction; Stat5 protein; Subgroup; Survival Rate; Testing; Therapeutic; Transcriptional Activation; Transgenic Model; Transgenic Organisms; Work; blocking factor; inducible Cre; inhibitor; knock-down; leukemia; leukemogenesis; loss of function mutation; mouse model; mutant; myeloblast; neutrophil; novel; novel therapeutic intervention; novel therapeutics; pharmacologic; prevent; programs; synergism; therapeutic development; transcription factor; transplant model; tumorigenesis; validation studies

PROJECT SUMMARY Acute Myeloid Leukemia (AML) is a lethal blood cancer, with a 5-year survival rate of only 25%. One driver of especially poor prognosis in AML is mutation of Colony Stimulating Factor 3 Receptor (CSF3R). The normal function of CSF3R is to promote the expansion of neutrophil precursors and their differentiation into mature neutrophils. In AML, mutant CSF3R is unable to drive differentiation. We hypothesize that this differentiation arrest is crucial to the aggressive biology of CSF3R-driven AML. In AML, differentiation arrest is often driven by genetic alterations in key hematopoietic transcription factors. Indeed, the vast majority of patients with CSF3R-mutant AML have co-occurring mutations in the transcription factor CEBPA, or translocations of the core binding factor (CBF) complex. These genetic alterations disrupt transcription factor function and perturb the epigenetic landscape of myeloid cells. Our data shows that the combination of mutant CSF3R with either mutant CEBPA or a CBF translocation produces an aggressive, poorly- differentiated myeloid leukemia. Furthermore, we find that mutant CEBPA alters the balance of signaling downstream of CSF3R through STAT proteins, to favor proliferative programs at the expense of pro- differentiation programs. Finally, CBF translocations suppress the expression of CEBPA, suggesting that CEBPA mutation or dysregulation is a common mechanism of differentiation arrest in CSF3R-driven AML. We hypothesize that CEBPA mutations and CBF translocations act through altered STAT signaling and epigenetic dysfunction to disrupt the transcription of differentiation-associated genes. We will test this hypothesis through two specific aims: 1) understand the functional significance of STAT dysregulation in CSF3R- mutant AML, and 2) identify a common mechanism of differentiation blockade in CSF3R-mutant AML. Successful completion of these studies will provide us with a mechanistic understanding of oncogene synergy in this poor prognosis CSF3R-mutant AML subgroup. This will enable the future development of rational therapeutic approaches to prevent disease relapse.

项目总结