Pathomechanisms inducing aberrant self-renewal and chemoresistance in GPR56high DNMT3A, NPM1, and FLT3-ITD triple mutated acute myeloid leukemia.

诱导 GPR56 高 DNMT3A、NPM1 和 FLT3-ITD 三重突变急性髓系白血病异常自我更新和化疗耐药的病理机制。

• 批准号: 327094337
• 负责人: Dr. Caroline Pabst
• 金额: --
• 依托单位: Klinik für Hämatologie, Onkologie und Rheumatologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2016
• 资助国家: 德国
• 起止时间: 2015-12-31 至 2019-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/327094337?language=en
• 关键词: Pathomechanisms; inducing; aberrant; self; renewal

Acute myeloid leukemia (AML) frequently presents without cytogenetic alterations (cytogenetically normal (CN)-AML). In this genetic subgroup knowledge about molecular genetic aberrations has become crucial for our understanding of the underlying pathomechanisms and for risk stratification to guide therapy decisions. DNMT3A, NPM1, and FLT3 belong to the most frequently mutated genes in CN-AML, but little is known about the co-occurrence of all three mutations (hereafter called triple AML DNMT3A/NPM1/FLT3-ITD). We found that triple AML is characterized by very high leukemia stem cell frequencies, short survival, and a unique GPR56highCD34low immunophenotype. Based on the literature and our findings we hypothesize that triple AML represents a distinct subgroup of CN-AML, in which these three mutations synergize to induce self-renewal and chemoresistance pathways. We propose to elucidate these pathomechanisms in three steps. First, we will analyze and model the transcriptomic signature induced by these three mutations in primary patient samples, inducible triple knock-in mouse models, and in genetically engineered human CD34+ cells. Using functional in vitro and in vivo assays we will determine which of the genes specifically upregulated in triple AML confer self-renewal and chemoresistance. Finally, we aim to use these novel findings to develop therapeutic approaches to specifically target leukemia stem cells in triple mutated AML. Taken together, this project aims to identify and characterize key regulators of self-renewal and chemoresistance in triple mutated AML DNMT3A/NPM1/FLT3-ITD.

急性髓性白血病（AML）通常表现为无细胞遗传学改变（细胞遗传学正常（CN）-AML）。在这个遗传亚群中，分子遗传畸变的知识对于我们理解潜在的病理机制和风险分层以指导治疗决策已经变得至关重要。DNMT 3A、NPM 1和FLT 3属于CN-AML中最常见的突变基因，但对所有三种突变的共同出现知之甚少（下文称为三重AML DNMT 3A/NPM 1/FLT 3-ITD）。我们发现，三重AML的特点是非常高的白血病干细胞频率，生存期短，和一个独特的GPR 56 highCD 34 low免疫表型。基于文献和我们的研究结果，我们假设三重AML代表了CN-AML的一个独特亚组，其中这三种突变协同诱导自我更新和化疗耐药途径。我们建议分三步阐明这些病理机制。首先，我们将分析和建模的转录组签名诱导的这三个突变在原代患者样本，诱导型三重敲入小鼠模型，并在基因工程改造的人CD 34+细胞。使用功能性体外和体内试验，我们将确定哪些基因在三重AML中特异性上调，从而赋予自我更新和化疗耐药性。最后，我们的目标是利用这些新的发现来开发治疗方法，以特异性靶向三重突变AML中的白血病干细胞。总之，该项目旨在鉴定和表征三重突变AML DNMT 3A/NPM 1/FLT 3-ITD中自我更新和耐药性的关键调节因子。