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

BCL-2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BCL-2家族的一个孤儿，与BAX和巴克具有广泛的序列相似性，但其分子功能仍然只有部分了解。BOK在人类癌症中通过拷贝数损失而反复缺失，表明具有肿瘤抑制功能。在第一个资助期内，我们发现BOK的缺失加重了实验小鼠的白血病发展，并且原发性人类白血病样本经常表现出低BOK mRNA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细胞和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患者和原发性小鼠白血病样本的数据集来阐明BOK抑制的分子机制，并着手克服这种抑制。为了更好地理解BOK作为治疗反应的生物标志物的可能作用，我们将通过流式细胞术定量白血病样本中的BOK水平，并利用这些数据进行计算机模拟治疗预测。总之，该建议剖析了BOK在造血干/祖细胞中的作用，以更好地理解其在干/祖细胞稳态和白血病发展中的作用。

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.