CD40 ligand upregulates expression of the IL-3 receptor and stimulates proliferation of B-lineage acute lymphoblastic leukemia cells in the presence of IL-3

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Abstract
The proliferative response of B cell precursor acute lymphoblastic leukemia (BCP-ALL) cells to IL-3 is dependent on the expression of functional IL-3 receptors (IL-3R). Here we report that CD40 ligand (CD40L) in the presence of recombinant IL-3 increased proliferation of BCP-ALL cells by upregulating expression of IL-3R. Upregulation of IL-3R in BCP-ALL cells was observed as early as 1 h after treatment with CD40L, and a 50- to 500-fold increase of IL-3R expression after 24 h was detected in all 12 cases studied. Moreover, expression of receptors for IL-7 (IL-7R) and stem cell factor (SCF-R, c-Kit) was also induced by CD40L in the majority of BCP-ALL cases examined; however, levels of induction were low compared to those for IL-3R. To test the functional activity of upregulated receptors for IL-3, SCF and IL-7, we evaluated the proliferation and growth of BCP-ALL cells cultured in serum-free media with CD40L plus these factors. When CD40L was added with either a single cytokine (IL-3, SCF and IL-7) or their combinations, cell proliferation was significantly increased as detected by DNA synthesis assay. Combinations of CD40L plus IL-3 and either SCF or IL-7 were able to support long-term growth of BCP-ALL cells for at least 8 weeks in three of the seven cases studied. Immunophenotyping and gene rearrangement studies indicated that cells in long-term cultures were monoclonal and retained their original phenotypes. The leukemic cells remained primarily dependent on the presence of IL-3 and its receptor for long-term growth, as shown by selective withdrawal of growth factors or antibody blockade of receptors. These results suggest an important role for CD40L in upregulating expression of IL-3R on BCP-ALL cells and enabling these cells to proliferate in long-term cultures in the presence of IL-3 and either SCF or IL-7.

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