UNRESPONSIVENESS OF PRIMITIVE CHRONIC MYELOID-LEUKEMIA CELLS TO MACROPHAGE INFLAMMATORY PROTEIN 1-ALPHA, AN INHIBITOR OF PRIMITIVE NORMAL HEMATOPOIETIC-CELLS

Most primitive hematopoietic cells appear to be normally quiescent in vivo, whereas their leukemic counterparts in patients with chronic mye loid leukemia (CML) are maintained in a state of rapid turnover. This difference is also seen in the long-term culture system, where control of primitive hematopoietic progenitor proliferation is mediated by in teractions of these cells with marrow-derived mesenchymal cells of the fibroblast lineage. We now show that exogenous addition of macrophage inflammatory protein 1alpha (MIP-1alpha) to normal long-term cultures can reversibly and specifically block the activation of ''primitive'' (high proliferative potential), but not ''mature'' (lower proliferati ve potential), progenitors in the adherent layer of these cultures. Mo reover, addition of MIP-1beta after primitive-progenitor activation ca n prevent the subsequent return of these cells to a quiescent state a few days later as shown previously in similar experiments using antibo dies to transforming growth factor beta. This suggests that the level of MIP-1alpha (or a related MIP-1alpha agonist) produced in LTCs, like the level of transforming growth factor beta, may be necessary, but i s not on its own sufficient, to mediate the inhibitory activity of the regulatory cells in the adherent layer. Addition of MIP-1alpha to sim ilar long-term cultures containing normal marrow adherent layers but s upporting exclusively neoplastic (CML) hematopoiesis did not block the cycling of primitive neoplastic progenitors. A defect in the responsi veness of CML cells to MIP-1alpha (or a similarly acting chemokine) wo uld explain their deregulated proliferative behavior in this model and , by extrapolation to the in vivo setting, suggests a molecular mechan ism whereby the leukemic clone may become amplified at the stem-cell l evel. In addition, these findings suggest approaches to the therapy of CML, using inhibitors such as MIP-1alpha for the protection of primit ive normal cells.