MYELOID DEVELOPMENT IS SELECTIVELY DISRUPTED IN PU.1 NULL MICE

The ets family transcription factor PU.1 is expressed in monocytes/mac rophages, neutrophils, mast cells, B cells, and early erythroblasts, b ut not in T cells. We have recently shown that PU.1 gene disruption re sults in mice with no detectable monocytes/macrophages and B cells but T-cell development is retained. Although neutrophil development occur red in these mice, it was delayed and markedly reduced. We now proceed to demonstrate that PU.1 null hematopoietic cells fail to proliferate or form colonies in response to macrophage colony-stimulating factor (M-CSF), granulocyte CSF (G-CSF), and granulocyte/macrophage CSF (GM-C SF). In contrast, PU.1 null cells did proliferate and form colonies in response to interleukin-3 (IL-3), although the response was reduced a s compared with control littermates. Compared with control cells, PU.1 null cells had minimal expression of G-and GM-CSF receptors and no de tectable M-CSF receptors. The size of individual myeloid colonies prod uced from PU.1 null primitive and committed myeloid progenitors in the presence of IL-3, IL-6, and stem cell factor (SCF) were reduced compa red with controls. Under these conditions, PU.1 null progenitors produ ced neutrophils but not monocytes/macrophages. These observations sugg est that PU.1 gene disruption induces additional cell-autonomous effec ts that are independent of the alterations in myeloid growth factor re ceptor expression. Our results demonstrate that PU.1 gene disruption a ffects a number of developmentally regulated hematopoietic processes t hat can, at least in part, explain the changes in myeloid development and reduction in myeloid and neutrophil expansion observed in PU.1 nul l mice. (C) 1998 by The American Society of Hematology.