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It was hypothesized that contact between chronic lymphocytic leukaemia (CLL) B‐cells and marrow stromal cells impact both cell types. To test this hypothesis, we utilized a long‐term primary culture system from bone biopsies that reliably generates a mesenchymal stem cell (MSC). Co‐culture of MSC with CLL B‐cells protected the latter from both spontaneous apoptosis and drug‐induced apoptosis. The CD38 expression in previously CD38 positive CLL B‐cells was up‐regulated with MSC co‐culture. Upregulation of CD71, CD25, CD69 and CD70 in CLL B‐cells was found in the co‐culture. CD71 upregulation was more significantly associated with high‐risk CLL, implicating CD71 regulation in the microenvironment predicting disease progression. In MSC, rapid ERK and AKT phosphorylation (within 30 min) were detected when CLL B‐cells and MSC were separated by transwell; indicating that activation of …