CD137L Signalling induces Differentiation of Primary Acute Myeloid Leukemia Cells

Abstract

The ligand for CD137 is expressed on hematopoietic progenitor cells and antigen-presenting cells such as monocytes, dendritic cells and B cells. Reverse signalling of CD137 ligand into the cell delivers a potent activating signal that results in the differentiation of hematopoietic progenitor cells into macrophages, and monocytes into dendritic cells. CD137 ligand is also expressed on acute myeloid leukaemia cells, which characteristically possess a maturation block that leads to arrested differentiation and malignancy. We hypothesized that CD137 ligand reverse signalling via stimulation with CD137 may also induce differentiation of the transformed myeloid cells in acute myeloid leukaemia. Primary acute myeloid leukaemia blasts isolated from either the bone marrow or peripheral blood of patients at time of diagnosis were stimulated with a recombinant CD137 protein in vitro. Reverse signalling through CD137 ligand induced differentiation of these leukemic blasts based on morphology, immunophenotype, cellular functions such as phagocytosis and proliferation, and cytokine release. These differentiated cells functionally demonstrated a more potent T cell co-stimulatory capacity as evidenced by up-regulation of co-stimulatory molecules, induction of increased T cell proliferation and cytokine release. These results suggest that CD137, as a single factor, is able to induce differentiation of the immature blasts in acute myeloid leukaemia into more effective antigen-presenting cells with enhanced T cell co-stimulatory potential.