Evasion from apoptosis is one of the less investigated hallmarks of cancer progression. The Bcr-Abl oncogene facilitates cytokine-independent growth of hematopoietic cells, which results in their enhanced proliferation and evasion from apoptosis. This process ultimately leads to chronic myeloid leukemia (CML). We recently reported that one mechanism by which Bcr-Abl expression promotes evasion from apoptosis in vitro is through the inhibition of FOXO3a-dependent transcription of several pro-apoptotic factors including TRAIL, as well as Bim and Hrk. The overall objective of this proposal is to elucidate the physiological role of FOXO3a and its downstream targets, TRAIL, Bim and Hrk, in Bcr-Abl-induced evasion from apoptosis and their involvement in Bcr-Abl-induced myeloproliferative disorders (MPD) in vivo. As is detailed in this proposal, we hypothesize that FOXO3a-dependent, Bcr-Abl-induced regulation of TRAIL, Bim and Hrk is a novel mechanism for regulating the tumorigenic activity of Bcr-Abl in vivo. Additionally, we posit that coordinate regulation of TRAIL, Bim and Hrk promotes Bcr-Abl-induced leukemia. Finally, we propose that Bcr-Abl supports evasion from apoptosis by instigating the proteasomal degradation of FOXO3a. Therefore, we hypothesize that targeting FOXO3a may be a therapeutic strategy to induce tumor-selective apoptosis in Bcr-Abl transformed cells.
The Specific Aims of this proposal are: 1) to determine the biological significance of FOXO3a transcription factor activity and consequent regulation of TRAIL expression in promoting Bcr-Abl-induced transformation of hematopoietic cells, 2) to determine whether Bcr-Abl also regulates Bim and Hrk expression in a FOXO3a dependent manner as a mechanism for apoptotic evasion in leukemic hematopoietic cells, 3) to determine the role of the proteasomal pathway in Bcr-Abl-mediated down-regulation of FOXO3a transcription factor. We will utilize diverse approaches to carry out these studies including molecular biology, cell biology, murine models for tumorigenicity and murine model for Bcr-Abl-induced leukemia. Taken together, these studies will lead to a better understanding of the mechanisms involved in leukemogenesis in general and to the characterization of novel molecular targets for treatment of CML. Finding a novel target is especially critical given that resistance to the currently used STI-571 therapy is emerging as a common problem.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
Project #
Application #
Study Section
Cancer Etiology Study Section (CE)
Program Officer
Duglas-Tabor, Yvonne
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Beth Israel Deaconess Medical Center
United States
Zip Code
Bhasin, Manoj K; Ndebele, Kenneth; Bucur, Octavian et al. (2016) Meta-analysis of transcriptome data identifies a novel 5-gene pancreatic adenocarcinoma classifier. Oncotarget 7:23263-81
Bucur, Octavian; Gaidos, Gabriel; Yatawara, Achani et al. (2015) A novel caspase 8 selective small molecule potentiates TRAIL-induced cell death. Sci Rep 5:9893
Bucur, Octavian; Stancu, Andreea Lucia; Muraru, Maria Sinziana et al. (2014) PLK1 is a binding partner and a negative regulator of FOXO3 tumor suppressor. Discoveries (Craiova) 2:
Pennarun, B; Gaidos, G; Bucur, O et al. (2013) killerFLIP: a novel lytic peptide specifically inducing cancer cell death. Cell Death Dis 4:e894
Bucur, Octavian; Stancu, Andreea Lucia; Goganau, Ioana et al. (2013) Combination of bortezomib and mitotic inhibitors down-modulate Bcr-Abl and efficiently eliminates tyrosine-kinase inhibitor sensitive and resistant Bcr-Abl-positive leukemic cells. PLoS One 8:e77390
Bucur, Octavian; Pennarun, Bodvael; Stancu, Andreea Lucia et al. (2013) Poor antibody validation is a challenge in biomedical research: a case study for detection of c-FLIP. Apoptosis 18:1154-62
Bucur, O; Stancu, A L; Khosravi-Far, R et al. (2012) Analysis of apoptosis methods recently used in Cancer Research and Cell Death & Disease publications. Cell Death Dis 3:e263
Singh, Amrik; Plati, Jessica; Khosravi-Far, Roya (2011) Harnessing the tumor suppressor function of FOXO as an alternative therapeutic approach in cancer. Curr Drug Targets 12:1311-21
Dewar, Rajan; Chen, Sing-Tsung; Yeckes-Rodin, Heather et al. (2011) Bortezomib treatment causes remission in a Ph+ALL patient and reveals FoxO as a theranostic marker. Cancer Biol Ther 11:552-8
Plati, Jessica; Bucur, Octavian; Khosravi-Far, Roya (2011) Apoptotic cell signaling in cancer progression and therapy. Integr Biol (Camb) 3:279-96

Showing the most recent 10 out of 17 publications