Dissecting molecular basis and cellular heterogeneity of slow progressing 'smoldering' AMLs of the elderly

剖析老年人缓慢进行性“闷烧”AML 的分子基础和细胞异质性

• 批准号: 387740555
• 负责人: Professorin Dr. Christine Dierks
• 金额: --
• 依托单位: Heidelberg Institute for Stem Cell Technology and Experimental Medicine gGmbH
• 依托单位国家: 德国
• 项目类别: Research Units
• 财政年份: 2017
• 资助国家: 德国
• 起止时间: 2016-12-31 至 2020-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/387740555?language=en
• 关键词: Dissecting; molecular; basis; cellular; heterogeneity

Acute Myeloid leukemia is an aggressive and highly complex disease caused by a combination of genetic lesions likely originating in normal hematopoietic stem cells. Typically patients present with a nearly exponential increase of leukocytes and blasts in the peripheral blood resulting in a lethal leukostasis within days. In elderly patients, or in patients with secondary AMLs, the course of the AML disease is often less aggressive, and sometimes untreated patients show stable blast and leukocyte counts over several months. Interestingly, some of those AML patients have higher blast counts in the PB than in the BM. These rare smoldering or slow progressing AMLs are of special interest, as they might represent an earlier disease stage of AML with aberrant mobilization of blasts into the peripheral blood due to failure of the bone marrow niche or altered regulation of homing receptors like CXCR4Since these types of AML in the elderly are rare and understudied, the mechanistic basis for these AMLs remains poorly understood and enigmatic. Within this Forschergruppe, we (A08) will first characterize more than 20 smoldering/slow progressing AML by detailed flow cytometric analysis with the inclusion of leukemic stem cell (LSC) markers as well as CXCR4, which may serve as a biomarker for these AMLs. We will determine the mutational landscape to these diseases by exome sequencing and will functionally identify LSC containing populations by transplantation into immune-compromised recipient mice. These LSCpos and LSCneg sub-populations will then be molecularly characterized at the genome wide level using a multi-omics approach. This includes determination of the methylome, transcriptome and mapping of chromatin accessibility. Correlation of these genome wide data sets using bioinformatics and computational approaches will reveal the overall molecular landscapes of LSCs and blasts in these AMLs with the goal to identify novel biomarkers for stratification and novel targets to therapeutically target this disease. Finally, we will specifically analyse MYC and a novel super-enhancer driving this key transcription factor in normal hematopoietic and AML stem cells. Together with the other EPIGRAM partners we will not only determine changes in the epigenetic landscape during leukemogenesis and LSC formation and function, but will focus specifically onto the MYC enhancer network as well as up- and downstream events, which are likely influencing aggressiveness, and therapy response. Altogether, we aim to explore the so far little explored smoldering AMLs of the elderly at a detailed genomic level, but are also studying the cause of differential blast mobilization and the role of CXCR4 as well as epigenetic control of MYC via its super-enhancer in AMLs. This project will not only reveal novel insights into the molecular make up of such indolent AMLs, but also may provide novel stratification and therapy tools to better characterize and target this subtype of AML.

急性髓系白血病是一种侵袭性和高度复杂的疾病，由可能起源于正常造血干细胞的遗传病变的组合引起。通常，患者外周血中的白细胞和原始细胞呈现接近指数增加，导致数天内致命的白细胞停滞。在老年患者或继发性AML患者中，AML疾病的病程通常不那么具有侵袭性，有时未经治疗的患者在几个月内显示稳定的原始细胞和白细胞计数。有趣的是，这些AML患者中的一些患者在PB中的原始细胞计数高于BM。这些罕见的闷烧或进展缓慢的急性髓性白血病（AML）特别令人感兴趣，因为它们可能代表急性髓性白血病（AML）的早期疾病阶段，由于骨髓生态位的失败或CXCR 4等归巢受体的调节改变，原始细胞异常动员进入外周血。由于老年人中的这些类型的急性髓性白血病很少见且研究不足，因此这些急性髓性白血病的机制基础仍然知之甚少且神秘莫测。在本研究组中，我们（A08）将首先通过详细的流式细胞术分析（包括白血病干细胞（LSC）标志物以及CXCR 4，其可作为这些AML的生物标志物）来表征20多例阴燃/缓慢进展的AML。我们将通过外显子组测序来确定这些疾病的突变景观，并通过移植到免疫受损的受体小鼠中来功能性地鉴定含有LSC的群体。然后，使用多组学方法在全基因组水平上对这些LSCpos和LSCneg亚群进行分子表征。这包括甲基化组、转录组的测定和染色质可及性的作图。使用生物信息学和计算方法对这些全基因组数据集进行关联将揭示这些AML中LSC和原始细胞的总体分子景观，目的是鉴定用于分层的新生物标志物和治疗靶向该疾病的新靶标。最后，我们将专门分析MYC和一种新型的超级增强子，它在正常造血干细胞和AML干细胞中驱动这种关键转录因子。与其他EPIGRAM合作伙伴一起，我们不仅将确定白血病发生和LSC形成和功能期间表观遗传景观的变化，而且将特别关注MYC增强子网络以及可能影响攻击性和治疗反应的上游和下游事件。总之，我们的目标是在详细的基因组水平上探索迄今为止很少探索的老年人闷烧AML，但也正在研究差异原始细胞动员的原因和CXCR 4的作用以及MYC通过其超级增强子在AML中的表观遗传控制。该项目不仅将揭示这种惰性AML的分子组成的新见解，而且还可能提供新的分层和治疗工具，以更好地表征和靶向这种AML亚型。