| Autor: |
Tonino SH; a Department of Hematology , Academic Medical Center , Amsterdam , The Netherlands.; b Lymphoma and Myeloma Center Amsterdam (LYMMCARE) , Amsterdam , The Netherlands., Mulkens CE; c Laboratory for Experimental Immunology, Academic Medical Center , Amsterdam , The Netherlands., van Laar J; c Laboratory for Experimental Immunology, Academic Medical Center , Amsterdam , The Netherlands., Derks IA; c Laboratory for Experimental Immunology, Academic Medical Center , Amsterdam , The Netherlands., Suo G; d Division of Hematology-Oncology, Department of Medicine , Moores Cancer Center, University of California , San Diego, La Jolla , CA , USA., Croon-de Boer F; e Department of Internal Medicine , Ikazia Hospital , Rotterdam , The Netherlands., van Oers MH; a Department of Hematology , Academic Medical Center , Amsterdam , The Netherlands.; b Lymphoma and Myeloma Center Amsterdam (LYMMCARE) , Amsterdam , The Netherlands., Eldering E; b Lymphoma and Myeloma Center Amsterdam (LYMMCARE) , Amsterdam , The Netherlands.; c Laboratory for Experimental Immunology, Academic Medical Center , Amsterdam , The Netherlands., Wang JY; d Division of Hematology-Oncology, Department of Medicine , Moores Cancer Center, University of California , San Diego, La Jolla , CA , USA., Kater AP; a Department of Hematology , Academic Medical Center , Amsterdam , The Netherlands.; b Lymphoma and Myeloma Center Amsterdam (LYMMCARE) , Amsterdam , The Netherlands. |
| Abstrakt: |
In chronic lymphocytic leukemia (CLL), strategies to overcome drug resistance due to p53 dysfunction are highly needed. Platinum-based compounds such as cisplatinum (CDDP) are active in fludarabine-refractory CLL through a largely unknown mechanism. We analyzed the mechanism of action of CDDP in the context of p53 dysfunctionality. In vitro treatment with CDDP did not induce death in quiescent CLL cells, but did induce apoptosis in CD40-ligand (and CpG) stimulated and proliferating cells, irrespective of p53 function. In the p53 dysfunctional prolymphocytic cell-line MEC1, CDDP treatment resulted in apoptosis, cell cycle arrest and ABL1-dependent expression of TAp73, CDKN1A, PUMA and BID. TAp73 RNA-interference decreased sensitivity to CDDP. Finally, both in vitro stimulated CLL cells and lymph node (LN) derived CLL cells showed increased TAp73 expression in comparison with quiescent peripheral blood derived cells. Activity of CDDP may therefore be mediated by TAp73, especially in the context of activation such as occurs in the LN microenvironment. |
