Characterization of BOK in hematopoietic stem/progenitor cell fitness, stress response and leukemic transformation

BOK 在造血干/祖细胞适应性、应激反应和白血病转化中的表征

• 批准号: 245725325
• 负责人: Professor Dr. Philipp Jost
• 金额: --
• 依托单位: Klinische Abteilung für Onkologie
• 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/245725325?language=en
• 关键词: Characterization; BOK; hematopoietic; stem; progenitor

The BCL-2 family controls the survival of cells by regulating the integrity of the mitochondrial outer membrane. BOK is an orphan BCL-2 family member exhibiting extensive sequence similarity to BAX and BAK, however its molecular functions remain only partially understood. BOK is recurrently deleted by copy number losses in human cancer suggesting a tumor suppressive function. During the first funding period, we showed that deletion of BOK aggravated leukemia development in experimental mice and that primary human leukemia samples frequently exhibited low BOK mRNA expression. Based on these findings and in an effort to better delineate a possible tumor suppressive function of BOK, we propose to study the cellular fitness and stress response of hematopoietic stem and progenitor cells. In addition, we will utilize datasets from human AML patients and primary murine leukemia samples to elucidate the molecular mechanism of BOK repression and we set out to pharmacologically overcome this repression. To better understand the possible role of BOK as a biomarker for treatment response, we will quantify BOK levels by flow cytometry in leukemic samples and utilize these data for in silico treatment prediction. Together, this proposal dissects the role of BOK in hematopoietic stem/progenitor cells to better understand its role in stem/progenitor cell homeostasis and leukemia development.

Bcl2家族通过调节线粒体外膜的完整性来控制细胞的存活。BOK是一个孤立的BCL-2家族成员，与Bax和BAK具有广泛的序列相似性，但其分子功能尚不完全清楚。BOK在人类癌症中因拷贝数丢失而被反复删除，这表明BOK具有肿瘤抑制功能。在第一个资助期，我们发现BOK基因的缺失加剧了实验小鼠的白血病发展，并且原代人类白血病样本经常表现出低水平的BOK基因表达。基于这些发现，为了更好地描述BOK可能的肿瘤抑制功能，我们建议研究造血干和造血祖细胞的细胞适应性和应激反应。此外，我们将利用来自人类AML患者和原代小鼠白血病样本的数据集来阐明BOK抑制的分子机制，并着手从药物上克服这种抑制。为了更好地了解BOK作为治疗反应生物标志物的可能作用，我们将通过流式细胞术对白血病样本中的BOK水平进行量化，并利用这些数据进行计算机治疗预测。总之，这项建议剖析了BOK在造血干/祖细胞中的作用，以更好地了解其在干/祖细胞动态平衡和白血病发生中的作用。