CXCR4 mediates the homing of B cell progenitor acute lymphoblastic leukaemia cells to the bone marrow via activation of p38MAPK.
The mechanisms regulating the migration of leukaemic cells between the blood and bone marrow compartments remain obscure, but are of fundamental importance for the dissemination of the disease. This study investigated the in vivo homing of human B cell progenitor acute lymphoblastic leukaemia (ALL) cells to the femoral bone marrow of non-obese diabetic severe combined immunodeficient (NOD/SCID) mice. It was demonstrated that patient ALL cells use the chemokine axis, chemokine (CXC motif) receptor 4 (CXCR4)/ chemokine (CXC motif) ligand 12 (CXCL12), to home to the femoral marrow. CXCL12-mediated signalling through p38 mitogen-activated protein kinase (MAPK) was required for optimal homing. In contrast, the homing of normal peripheral blood CD34(+) cells and the cytokine-dependent CD34(+) cell line Mo7e was independent of p38MAPK, consistent with the dependence of these cells, as well as normal CD34(+) CD19(+) B cell progenitors, on PI-3K/AKT signalling. Altogether, our data provide clarification of the direct role of CXCL12 in the bone marrow homing of ALL cells and demonstrate unique signalling molecule usage that may have therapeutic implications for this disease.
Juarez
Julius G
JG
Westmead Institute for Cancer Research, University of Sydney at the Westmead Millennium Institute, Westmead Hospital, Westmead, NSW, Australia.
Thien
Marilyn
M
Dela Pena
Aileen
A
Baraz
Rana
R
Bradstock
Kenneth F
KF
Bendall
Linda J
LJ