Regulation of glucocorticoid-evoked apoptosis in human leukemic CEM cells by Bcl11b

Apoptotic cell death is essential for embryonic development, tissue homeostasis, and a well-functioning immune system. Impaired apoptosis is both critical in cancer development and is a major barrier to effective treatment. In response to diverse intracellular damage signals, including those evoked by cancer therapy, the cell's decision to undergo apoptosis is determined by interactions between pro-survival and pro-apoptotic proteins and their relative expression levels. Glucocorticoid (GC) are steroid hormones that provoke a wide array of effects on cells. Synthetic GCs such as dexamethasone (Dex), serve as therapeutic agents for some lymphoid leukemias because of their ability to induce transcriptional changes and trigger apoptosis via activation of the Glucocorticoid Receptor (GR). Using a pair of human leukemic T cell lines: CEM-C7-14 (GC sensitive) and CEM-C1-15 (GC-resistant), our laboratory has shown that Dex-mediated E4BP4 upregulation is a crucial step in activation of apoptosis. Recently, E4BP4 was shown to be a defining factor for natural killer (NK) cell development. The B-cell lymphoma 11B (Bcl11b) gene plays a crucial role in thymopoiesis and has been associated with hematopoietic malignancies. Bcl11b is a lineage-specific transcription factor expressed in various cell types and its expression is important for development of T cells, neurons and others, while its deletion is associated with differentiation of T cells to the natural killer lineage, suggesting that Bcl11b acts upstream from E4BP4. The hypothesis of my research is that Bcl11b suppression correlates with upregulation of E4BP4 and apoptosis of leukemic cells in response to anti-leukemic agents. Expression levels of Bcl11b in response to Dex was evaluated by qRT-PCR in CEM cell lines, and were correlated with published data on E4BP4 expression. The data confirmed that Bcl11b is downregulated in CEM sensitive cells upon Dex treatment while Bcl11b expression was not significantly altered in the GC resistant CEM C1-15 cells.