Expression of activated M-Ras in hemopoietic stem cells initiates leukemogenic transformation, immortalization and preferential generation of mast cells

Abstract

Cultures of purified hemopoietic stem cells transduced with an activated mutant of M-Ras contained abnormal cells that, despite the presence of only low levels of growth factors, generated large, dense colonies of macrophages and blast cells. Cells from these colonies survived and grew continuously in the absence of growth factors and generated clonal cell-lines that were mainly composed of well-differentiated mast cells, with a low frequency of undifferentiated cells. When transplanted into sublethally irradiated syngeneic mice, four out of four such clones gave rise to a systemic mastocytosis and mast-cell leukemia. However, the donor clones also generated low percentages of cells with the morphological and cell-surface characteristics of erythrocytes, granulocytes, monocytes and T- and B-lymphocytes. These data indicate that signals downstream of activated M-Ras are sufficient to transform hemopoietic stem cells, and while preserving their capacity to generate other cell-lineages in vivo, result in preferential generation of mast cells.