Mechanisms of differentiation blockade in CSF3R-mutant AML

CSF3R 突变 AML 分化阻断机制

基本信息

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
项目类别：
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

项目摘要

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.

项目概要急性髓系白血病（AML）是一种致命的血液癌症，5年生存率仅为25%。一名司机 AML 的预后尤其差的是集落刺激因子 3 受体 (CSF3R) 的突变。正常的 CSF3R的功能是促进中性粒细胞前体的扩增及其分化为成熟粒细胞中性粒细胞。在 AML 中，突变的 CSF3R 无法驱动分化。我们假设这种分化逮捕对于 CSF3R 驱动的 AML 的侵袭性生物学至关重要。在 AML 中，分化停滞通常是由关键造血转录因子的基因改变驱动的。事实上，绝大多数患有 CSF3R 突变的 AML 患者在转录中同时存在突变。 CEBPA 因子，或核心结合因子 (CBF) 复合物的易位。这些基因改变扰乱了转录因子功能并扰乱骨髓细胞的表观遗传景观。我们的数据表明突变体 CSF3R 与突变体 CEBPA 或 CBF 易位的组合会产生攻击性的、较差的分化型粒细胞白血病。此外，我们发现突变的 CEBPA 改变了信号平衡通过 STAT 蛋白位于 CSF3R 下游，以牺牲促增殖程序为代价差异化计划。最后，CBF 易位抑制 CEBPA 的表达，表明 CEBPA 突变或失调是 CSF3R 驱动的 AML 分化停滞的常见机制。我们假设 CEBPA 突变和 CBF 易位通过改变 STAT 信号传导起作用表观遗传功能障碍会破坏分化相关基因的转录。我们将测试这个通过两个具体目标提出假设：1）了解 CSF3R 中 STAT 失调的功能意义突变型 AML，2) 确定了 CSF3R 突变型 AML 中分化阻断的常见机制。这些研究的成功完成将为我们提供对癌基因协同作用的机制理解在这种预后不良的 CSF3R 突变 AML 亚组中。这将使未来的发展更加理性预防疾病复发的治疗方法。