Project P8

"Characterization of the Bcl-2 family member Bok in leukemogenesis"

People involved: Philipp Jost, Ulrike Hoeckendorf

Keywords: Apoptosis, Bcl-2 family, BOK, leukemia, AML, mouse model

Bok is a Bax/Bak-like Bcl-2 family member, however little is know about its precise molecular function within the cell. Interestingly, genomic deletions of Bok were recently identified with high frequency in human cancers. Since resistance to apoptosis is a characteristic feature of acute myeloid leukaemia (AML), we determined Bok expression in human AML cells and found loss of Bok mRNA and protein expression in 5 out of 7 AML cell lines tested. In contrast, Bok is readily expressed in human primary haematopoietic stem/progenitor cells. Using a large cohort of primary AML patient samples, we found reduced Bok expression by gene-expression analysis in patients diagnosed with FLT3+/NPM1+ AML. To functionally validate the expression data, we utilized gene-targeted mice lacking Bok in a murine AML transplantation model and found accelerated leukaemia formation in the absence of Bok. We therefore hypothesize that pro-apoptotic Bok might serve as a tumour suppressor protein in haematopoietic stem/progenitor cells thereby protecting against leukaemogenesis. In this proposal, we want to determine how Bok impacts on apoptosis and proliferation of healthy haematopoietic progenitors and leukemic blast cells and characterize leukaemia development in Bok-/- mice in vivo. Together we hope to clarify how Bok protects cells from FLT3-dependent transformation thereby improving the molecular understanding of the function of Bok for haematopoiesis and leukaemogenesis.

Co-operations within FOR2036:
T. Kaufmann, Bern
G. Haecker, Freiburg
M. Erlacher, Freiburg