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Blood, Vol. 92 No. 5 (September 1), 1998:
pp. 1576-1585
Neutrophils Deficient in PU.1 Do Not Terminally Differentiate or
Become Functionally Competent
Karen L. Anderson,
Kent A. Smith,
Frederic Pio,
Bruce E. Torbett, and
Richard A. Maki
From The Burnham Institute and the Department of Immunology, The
Scripps Research Institute, La Jolla, CA.
PU.1 is an ets family transcription factor that is expressed
specifically in hematopoietic lineages. Through gene disruption studies
in mice we have previously shown that the expression of PU.1 is not
essential for early myeloid lineage or neutrophil commitment, but is
essential for monocyte/macrophage development. We have also shown that
PU.1-null (deficient) neutrophils have neutrophil morphology and
express neutrophil-specific markers such as Gr-1 and chloroacetate
esterase both in vivo and in vitro. We now demonstrate that although
PU.1-null mice develop neutrophils, these cells fail to terminally
differentiate as shown by the absence of messages for neutrophil
secondary granule components and the absence or deficiency of cellular
responses to stimuli that normally invoke neutrophil function.
Specifically, PU.1-deficient neutrophils fail to respond to selected
chemokines, do not generate superoxide ions, and are ineffective at
bacterial uptake and killing. The failure to produce superoxide could,
in part, be explained by the absence of the gp91 subunit of
nicotinamide adenine dinucleotide phosphate oxidase, as shown by our
inability to detect messages for the gp91phox
gene. Incomplete maturation of PU.1-deficient neutrophils is cell
autonomous and persists in cultured PU.1-deficient cells. Our results
indicate that PU.1 is not necessary for neutrophil lineage commitment
but is essential for normal development, maturation, and function of
neutrophils.
© 1998 by The American Society of Hematology.
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