FOXP3 can modulate TAL1 transcriptional activity through interaction with LMO2

Abstract

T-cell acute lymphoblastic leukemia (T-ALL) frequently involves aberrant expression of TAL1 (T-cell acute lymphocytic leukemia 1) and LMO2, oncogenic members of the TAL1 transcriptional complex. Transcriptional activity of the TAL1-complex is thought to have a pivotal role in the transformation of thymocytes and is associated with a differentiation block and self-renewal. The transcription factor Forkhead Box P3 (FOXP3) was recently described to be expressed in a variety of malignancies including T-ALL. Here we show that increased FOXP3 levels negatively correlate with expression of genes regulated by the oncogenic TAL1-complex in human T-ALL patient samples as well as a T-ALL cell line ectopically expressing FOXP3. In these cells, FOXP3 expression results in altered regulation of cell cycle progression and reduced cell viability. Finally, we demonstrate that FOXP3 binds LMO2 in vitro, resulting in decreased interaction between LMO2 and TAL1, providing a molecular mechanism for FOXP3-mediated transcriptional modulation in T-ALL. Collectively, our findings provide initial evidence for a novel role of FOXP3 as a tumor suppressor in T-ALL through modulation of TAL1 transcriptional activity.

Notch and NF-κB: Coach and Players of Regulatory T-Cell Response in Cancer

“…This picture can be further complicated by the arrival of Notch3 signals that can recruit on the Foxp3 promoter a new complex binding the p65/CSL-nested site close to the transcription start site of the Foxp3 promoter (Table 1 ) ( 14 ). More importantly, we can suggest that this Notch/p65 cooperation can be active also in the regulation of Foxp3 signaling in cancer cells ( 106 ), as recently described in thyroid cancer and T-ALL ( 15 , 16 ).…”

Foxp3 downregulation in NSCLC mediates epithelial-mesenchymal transition via NF-κB signaling

“…We next explored the mechanisms of Foxp3 regulation of the EMT process. Recent literature revealed that Foxp3 could modulate TAL1 transcriptional activity through interaction with LMO2 in T-ALL (15). In the present study, we found Foxp3 could interacted with LMO2 by co-IP assay, furthermore, we observed that the mRNA level of TAL1 was upregulated in both cell lines after Foxp3 downregulation.…”

“…Recent studies indicated that Foxp3 was also expressed in breast, lung, prostate and gastric cancer tissue (25)(26)(27)(28). Furthermore, the clinical roles and biological function of Foxp3 have been thoroughly studied in T-ALL and breast cancer (15,27). These results In the present study, we first evaluated the clinical significance of Foxp3 expression in NSCLC patients.…”

“…of Foxp3 as a tumor suppressor in T-cell acute lymphoblastic leukemia (T-ALL) (15). In breast cancer, Liu et al revealed that miR-146a/b could induce cell apoptosis and contributed to Foxp3-mediated tumor suppression during tumor progress (16).…”

Stem Cell Leukemia: how a TALented actor can go awry on the hematopoietic stage

“…As mentioned, TAL1 binds to E-box motifs (CANNTG) through heterodimerization with an Eprotein. The binding occurs preferentially to the E-box CAGATG, rather than the E-box CAGGTG that is favored by E-protein homodimers 80 Interestingly, a recent study proposed that the transcription factor FOXP3 can have a tumor suppressor role in T-ALL by binding to LMO2 and decreasing its interaction with TAL1 and consequently decreasing TAL1 transcriptional activity 85 .…”