| Autor: |
Ehrmann AS; Division of CLL, Department of Internal Medicine III, University Hospital of Ulm, Ulm, Germany.; Mechanisms of Leukemogenesis (B061), German Cancer Research Center (DKFZ), Heidelberg, Germany., Zadro A; Division of CLL, Department of Internal Medicine III, University Hospital of Ulm, Ulm, Germany., Tausch E; Division of CLL, Department of Internal Medicine III, University Hospital of Ulm, Ulm, Germany.; Comprehensive Cancer Center Ulm (CCCU), University Hospital of Ulm, Ulm, Germany., Schneider C; Division of CLL, Department of Internal Medicine III, University Hospital of Ulm, Ulm, Germany.; Comprehensive Cancer Center Ulm (CCCU), University Hospital of Ulm, Ulm, Germany., Stilgenbauer S; Division of CLL, Department of Internal Medicine III, University Hospital of Ulm, Ulm, Germany.; Comprehensive Cancer Center Ulm (CCCU), University Hospital of Ulm, Ulm, Germany., Mertens D; Division of CLL, Department of Internal Medicine III, University Hospital of Ulm, Ulm, Germany.; Mechanisms of Leukemogenesis (B061), German Cancer Research Center (DKFZ), Heidelberg, Germany. |
| Abstrakt: |
In chronic lymphocytic leukemia (CLL), TP53 mutations or deletions on chromosome 17p lead to adverse prognosis and reduced levels of miR-34a, which targets NOTCH1. Also, hyperactivated NOTCH1 signaling is crucial for CLL progression. Here we explored the interaction between p53, miR-34a, and NOTCH1 in CLL. We investigated the effect of p53 and miR-34a on NOTCH1 signaling and expression in CLL cells with altered TP53 . Our results indicate that miR-34a reduces NOTCH1 3' UTR activity but might not be a mediator between p53 signaling and NOTCH1. p53 activation increases miR-34a expression and NOTCH1 protein levels, correlating with decreased NOTCH1 and miR-34a levels in primary CLL cells with TP53 alterations. Some samples with high NOTCH1 levels presented increased BCL-2, suggesting an anti-apoptotic mechanism of a potentially direct p53-NOTCH1 relation in CLL. This study deepens the understanding of the p53-miR-34a-NOTCH1 signaling network, providing insights that could guide future therapeutic strategies for CLL. |
