Activation of the P38 MAPK Pathway Mediates Resistance to Ara-C y Bcr/Abl Positive Cells.

Abstract

The chimeric protein Bcr/Abl has been connected to several signalling pathways such as AKT, JNK or ERK1/2. Here, we present evidence showing that Bcr/Abl is able to modulate the p38 MAPK pathway. Transient transfection experiments indicated that over-expression of Bcr/Abl in 293T is able to activate p38 MAPK or induce p73 stabilization, suggesting that c-Abl and Bcr/Abl share some biological substrates. Interestingly, the control exerted by Bcr/Abl on the p38 MAPK pathway was not only mediated by the tyrosine kinase activity of Bcr/Abl. In fact, Bcr alone is able to induce P38 MAPK activation specifically through MKK3. Supporting these observations Chronic Myeloid Leukaemia-derived K562 cells or BaF 3 cells stably transfected with Bcr/Abl showed higher levels of phosphorylated p38 MAPK compared to Bcr/Abl-negative cells. Interestingly, Bcr/Abl-negative cells activated p38 MAPK in response to Ara-C, while Bcr/Abl-positive cells were unable to activate p38 MAPK. Furthermore, inhibition of p38 MAPK activation by SKF860002 induces a resistant phenotype in Bcr/Abl negative cells. Our results demonstrate that the interference of Bcr/Abl in the p38 MAPK pathway is a key mechanism for explaining resistance to Ara-C in Bcr/abl positive cells.