Chronic myeloid leukemia and allogeneic natural killer cells: a surprising dialogue

Chronic myeloid leukemia (CML) is a clonal multilineage myeloproliferative disease of stem cell origin characterized by the presence of the Bcr/Abl oncoprotein, a constitutively active tyrosine kinase. The actual treatment of CML patients in chronic phase is the specific abl kinase inhibitor imatinib mesylate that induces 90% of cytogenetic responses in early-phase patients. However, resistance in long-term treated patients occurs and the allogeneic stem cell transplantation remains the only curative treatment in resistant patients. Despite recent reports outlining the role of allogeneic natural killer (NK) cells as potent antileukemic effectors, the mechanisms controlling the leukemic target recognition and lysis by activated NK cells have not been well identified. The authors' experimental data obtained on appropriate cellular models identify diverse mechanisms that could explain the increased NK-cell susceptibility of Bcr/Abl targets to NK-mediated lysis. They further delineate unexpected effects of the inhibition of the tyrosine kinase activity on the cross-talk between NK and CML leukemic cells. The consequences of such discoveries are discussed in the context of combined treatments with antikinases as well as adoptive cellular therapy approaches in myeloid leukemia patients.