Unregulated proliferation of primitive chronic myeloid leukemia progenitors in the presence of normal marrow adherent cells

Abstract

Previous studies have shown that Philadelphia (Ph1) chromosome-positive chronic myeloid leukemia (CML) results from the abnormal expansion at the pluripotent stem cell level of a single clone of hemopoietic cells. Although it seems likely that this is related to the heightened proliferative activity characteristic of primitive CML progenitor cell types, the underlying mechanism is unknown. In this report we show that either normal or CML peripheral blood progenitors can be maintained on preestablished normal marrow adherent layers for periods of 1-2 months. Under these conditions numbers of both normal and neoplastic progenitors are usually higher in the adherent layer than in the nonadherent fraction. Moreover, the number of primitive progenitors of high proliferative potential present in the adherent layer is sufficient to allow their cycling status to be determined. Such measurements demonstrate that primitive normal progenitors of blood origin, when cultured in the presence of a preestablished adherent marrow feeder layer, go in and out of cycle after each medium change but in the absence of a feeder layer remain continuously in cycle. In contrast, primitive CML progenitors of either blood or marrow origin cycle continuously regardless of the presence or absence of an adherent feeder layer. We suggest that early expansion of the CML clone is related to an ability of the neoplastic stem cells to ignore or overcome a negative regulatory signal produced by nonneoplastic adherent marrow cells whose normal function is to maintain the stem cell reserve in a quiescent state.