Defective P38 MAPK Signalling Impairs Chemotactic but Not Proliferative Responses to SDF-1 in Acute Lymphoblastic Leukemia.

The chemokine SDF-1 regulates leukemic cell motility and proliferation but the importance of these functions in the growth and dissemination of leukemia is unclear. We examined SDF-1-mediated responses of cells from 27 cases of acute lymphoblastic leukemia (ALL). Although cells from the majority of cases showed chemotactic and proliferative responses to SDF-1, a subset of cases (18%) did not undergo chemotaxis in response to SDF-1 (unresponsive cases). These unresponsive cases also failed to increase b1 integrin-mediated adhesion to fibronectin or adhesion to bone marrow fibroblast layers. However the unresponsive cases could still elicit a calcium flux in response to SDF-1 and three of the four cases internalised the receptor, CXCR4, following exposure to SDF-1. In contrast, the CXCR4 antagonist, TC14012, inhibited proliferation of both responsive and unresponsive cases in stromal-dependent cultures, demonstrating that the unresponsive cases were still able to undergo proliferative responses to SDF-1. Examination of the signalling pathways activated by SDF-1 in responsive cells revealed increased phosphorylation of AKT, ERK and p38 MAPK 2 to 5 minutes following stimulation. However, cells from the unresponsive cases failed to phosphorylate p38 MAPK kinase when stimulated with SDF-1, while phosphorylation of AKT and ERK were comparable with that observed in responsive ALL cases. Inhibition of p38 MAPK by SB203500 completely inhibited the chemotaxis of responsive ALL cells to SDF-1 gradients suggesting that signalling through p38 MAPK is essential for ALL cell chemotaxis. Therefore it is likely that the absence of p38 MAPK phosphorylation in unresponsive cases underlies their lack of chemotaxis to this chemokine. The ability of the unresponsive cases to undergo SDF-1 driven proliferation in the absence of p38 MAPK phosphorylation suggests that, despite being absolutely required for chemotactic responses, induction of phosphorylation of p38 MAPK is not required for proliferative responses. No correlation was observed between CXCR4 expression and chemotactic function, in vitro migration into bone marrow stromal layers, and engraftment of leukemic cells in NOD/SCID mice. This study suggests that signalling through p38 MAPK is required for ALL cell chemotaxis, but not for proliferation, and that chemotactic responses to SDF-1 are not essential for leukemic cell engraftment.