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PML protein expression in hematopoietic and acute promyelocytic leukemia
cells
MT Daniel, M Koken, O Romagne, S Barbey, A Bazarbachi, M Stadler, MC Guillemin, L Degos, C Chomienne and H de The
Laboratoire d'Hematologie, CNRS 43, Centre Hayem, Paris, France.
Acute promyelocytic leukemia (APL) is thought to be caused by the t(15,17)
translocation that fuses the PML gene to that of the retinoic acid receptor
alpha (RAR alpha) and generates a PML/RAR alpha fusion protein. Yet,
paradoxically, APL cells are exquisitely sensitive to retinoic acid (RA),
as they terminally differentiate upon RA exposure. In this report, we have
examined the expression of PML and PML/RAR alpha in normal and APL cells.
By immunofluorescence or immunocytochemistry, we show that PML has a
speckled nuclear pattern of expression that contrasts with that of PML/RAR
alpha (mostly a micropunctuated nuclear pattern or a cytoplasmic
localization). The APL- derived cell line NB4 that expresses both the PML
and PML/RAR alpha genes also shows the fine micropunctuated nuclear
pattern, suggesting a dominant effect of the fusion protein over the
localization of wild- type PML. RA treatment of NB4 cells or clones
expressing PML/RAR alpha gradually leads to a PML pattern before apparent
morphologic maturation. In 14 untreated APL patients, the PML-reactive
proteins were cytoplasmic (by immunocytochemistry) or both cytoplasmic and
nuclear with a micropunctuated pattern (by immunofluorescence). Strikingly,
in 4 patients, after 1 to 2 weeks of RA therapy, the speckled nuclear PML
pattern reappeared concomitant with the onset of differentiation. These
results establish that fusion of PML to RAR alpha results in an altered
localization of PML that is reverted upon RA treatment. This observation,
which highlights the importance of PML, is likely to be a key to
unravelling the molecular mechanism of both leukemogenesis and RA-induced
differentiation of APL.
Volume 82,
Issue 6,
pp. 1858-1867,
09/15/1993
Copyright © 1993 by The American Society of Hematology

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