Characterization of pro- and anti-apoptotic Bcl-2 proteins regulating hematopoiesis and leukemogenesis in the context of RAS hyperactivation

RAS 过度激活背景下调节造血和白血病发生的促凋亡和抗凋亡 Bcl-2 蛋白的表征

• 批准号: 245729546
• 负责人: Privatdozentin Dr. Miriam Erlacher
• 金额: --
• 依托单位: Zentrum für Kinder- und Jugendmedizin
• 依托单位国家: 德国
• 项目类别: Research Units
• 财政年份: 2014
• 资助国家: 德国
• 起止时间: 2013-12-31 至 2021-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/245729546?language=en
• 关键词: Characterization; pro; anti; apoptotic; Bcl

Pro- and anti-apoptotic members of the Bcl-2 protein family and their balanced regulation are of crucial importance for generation, maintenance and function of the hematopoietic system. Although reasonably well defined in the mouse hematopoietic system, the many roles of Bcl-2 proteins in human hematopoiesis are still incompletely understood. In the current funding period, we are therefore investigating how Bcl-2 proteins contribute to proper functioning of the human hematopoietic system. We are focusing on pro-survival Bcl-2 proteins to identify the protein or protein combinations that are required to keep human hematopoietic stem and progenitor cells alive, both under steady state conditions and when put under stress. By doing so, we aim at defining the "minimal requirements" for stem cell survival and blood formation. In the follow-up project, we will investigate how composition and regulation of Bcl-2 proteins do change during malignant transformation. As a model system for the multistep process of tumorigenesis, we will use cells with constitutively activated RAS signaling. Constitutively activated RAS signaling (e.g. due to mutations in NRAS, KRAS, PTPN11, NF1 or CBL) in hematopoietic cells can either result in an apparently unaffected hematopoiesis (i.e. in patients with Noonan syndrome) or in polyclonal and transient myeloproliferation, as seen in a subset of Noonan syndrome patients. It can, however, also result in juvenile myelomonocytic leukemia (JMML), a highly aggressive myeloid childhood leukemia. Using cells derived from patients with Noonan syndrome (+/- myeloproliferation) or JMML, as well as corresponding mouse models, we propose to characterize if and how Bcl-2 proteins are deregulated in different stages of RAS-driven leukemic transformation and evaluate, in which disease stages it could be beneficial to treat patients with BH3-mimetics. We hypothesize that the profile of Bcl-2 protein deregulation changes during disease progression and that these changes contribute to the pathogenesis of myeloproliferation and JMML. We expect that these results will be transferable to some extent from Noonan syndrome, myeloproliferation and JMML to more complex types of cancer that are also driven by RAS activation.

Bcl2蛋白家族中的促凋亡和抗凋亡成员及其平衡调节对于造血系统的生成、维持和功能至关重要。尽管在小鼠的造血系统中得到了很好的定义，但对人类造血中的许多作用仍不完全清楚。因此，在目前的资助期内，我们正在研究Bcl-2蛋白如何有助于人类造血系统的正常运作。我们正专注于促进生存的Bcl-2蛋白，以确定在稳定条件下和在压力下维持人类造血干细胞和祖细胞存活所需的蛋白质或蛋白质组合。通过这样做，我们的目标是定义干细胞存活和造血的“最低要求”。在后续的项目中，我们将研究在恶性转化过程中，Bcl2蛋白的组成和调控是如何变化的。作为肿瘤发生多步骤过程的模型系统，我们将使用具有结构性激活的RAS信号的细胞。造血细胞中的结构性激活的RAS信号(例如，由于NRAS、KRAS、PTPN11、NF1或CBL的突变)可以导致明显未受影响的造血(即在Noonan综合征患者中)，或者导致多克隆和一过性骨髓增殖，如Noonan综合征患者的一个亚群所见。然而，它也可以导致幼年粒单核细胞白血病(JMML)，一种高度侵袭性的儿童髓系白血病。使用Noonan综合征(+/-骨髓增殖)或JMML患者的细胞以及相应的小鼠模型，我们建议表征在RAS驱动的白血病转化的不同阶段，Bcl2蛋白是否以及如何被解除调控，并评估在哪些疾病阶段，它可能有利于治疗具有BH3类似物的患者。我们推测，在疾病发展过程中，Bcl2蛋白失调性改变，这些改变参与了骨髓增殖和JMML的发病机制。我们预计，这些结果将在一定程度上从Noonan综合征、骨髓增生和JMML转移到更复杂的癌症类型，这些癌症也是由RAS激活驱动的。