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

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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.