| The transcription factor NF-kappaB is a critical cell death regulator. TAL1 is an oncoprotein in T acute lymphoblastic leukemia (T-ALL), which can activate or repress gene transcription. While TAL1 expression is linked to poor prognosis of T-ALL patients, the direct TAL1 target genes important for T-ALL pathogenesis and malignant manifestation remain to be elucidated. In my thesis project, I found that TAL1 binds to the NFKB1 promoter in vitro and in vivo and contributes to its basal repression in T-ALL cells. When these cells are exposed to an NF-kappaB activation stimulus, the TAL1-mediated repression is reversed by p65-NF-kappaB and ELF1-dependent transcriptional activation, causing marked increases in the expression of p50 protein that is encoded by NFKB1 and exchange of NF-kappaB dimers to those containing the p50 subunit. On subsequent exposure to genotoxic agents, an augmented NF-kappaB DNA binding to certain kappaB elements is observed, which correlates with increased synthesis of certain NF-kappaB-dependent genes, in particular p21cip1/kip1. Inhibition of p21cip1/kip1 expression sensitizes CEM T-ALL cells to genotoxic agents. Similar augmentation of NF-kappaB activity and p21cip1/kip1 induction is seen in three TAL1 + T-ALL cell lines, but not in TAL1 - T-ALL or other cell lines. Moreover, enhanced TAL1 expression correlated with a decreased NFKB1 expression in primary patient samples that also harbor LMO1 expression. My study identifies NFKB1 as a new target of TAL1 regulation and suggests that inhibition of NF-kappaB or p21cip1/kip1 might be beneficial for treatment of a subset of TAL1 + T-ALL patients. |
