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Blood, 1 December 2000, Vol. 96, No. 12, pp. 3894-3899
NEOPLASIA
The aberrant fusion proteins PML-RAR and PLZF-RAR
contribute to the overexpression of cyclin A1 in acute
promyelocytic leukemia
Carsten Müller,
Rong Yang,
Dorothy J. Park,
Hubert Serve,
Wolfgang E. Berdel, and
H. Phillip Koeffler
From the Division of Hematology/Oncology, Cedars-Sinai
Research Institute/UCLA School of Medicine, Los Angeles, CA, and the
Department of Medicine, Hematology/Oncology, University of
Münster, Münster, Germany.
Cyclin A1 is a newly discovered cyclin that is overexpressed in
certain myeloid leukemias. Previously, the authors found that the
frequency of cyclin A1 overexpression is especially high in acute
promyelocytic leukemia (APL). In this study, the authors investigated
the mechanism of cyclin A1 overexpression in APL cells and showed that
the APL-associated aberrant fusion proteins (PML-retinoic acid
receptor alpha [PML-RAR ] or PLZF-RAR) caused the increased
levels of cyclin A1 in these cells. The ectopic expression of either
PML-RAR or PLZF-RAR in U937 cells, a non-APL myeloid cell line,
led to a dramatic increase of cyclin A1 messenger RNA and protein. This
elevation of cyclin A1 was reversed by treatment with
all-trans retinoic acid (ATRA) in cells expressing
PML-RAR but not PLZF-RAR. ATRA also greatly reduced the high
levels of cyclin A1 in the APL cell lines NB4 and UF-1. No effect of
ATRA on cyclin A1 levels was found in the ATRA-resistant NB4-R2 cells. Further studies using ligands selective for various retinoic acid receptors suggested that cyclin A1 expression is negatively regulated by activated RAR. Reporter assays showed that PML-RAR led to activation of the cyclin A1 promoter. Addition of ATRA inhibited PML-RAR-induced cyclin A1 promoter activity. Taken together, our
data suggest that PML-RAR and PLZF-RAR cause the high-level expression of cyclin A1 seen in acute promyelocytic leukemia.
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