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Constitutive Expression of the Promyelocytic Leukemia-Associated
Oncogene PML-RAR in TF1 Cells: Isoform-Specific and Retinoic
Acid-Dependent Effects on Growth, bcl-2 Expression, and Apoptosis
James L. Slack and
Min Yu
From the Division of Medicine and the Departments of Hematologic
Oncology/Bone Marrow Transplantation, Roswell Park Cancer Institute,
Buffalo, NY.
Two major isoforms of PML-RAR are associated with
(15;17)-positive acute promyelocytic leukemia (APL); however,
functional differences between these isoforms have been difficult to
define, and the molecular mechanism by which each isoform contributes to the pathogenesis of APL is not fully understood. To address these
issues, the `short' (S) and `long' (L) isoforms of PML-RAR were
constitutively expressed in the factor-dependent human erythroleukemia cell line, TF1. Expression of the L, but not the S, isoform inhibited growth of these cells in the presence of granulocyte-macrophage colony-stimulating factor (GM-CSF). In the absence of GM-CSF, the S
isoform partially protected against apoptosis, while the L isoform
accelerated cell death. Treatment with all-trans retinoic acid
(ATRA) inhibited cell growth and caused apoptosis only in PML-RAR-expressing cells, and these effects of ATRA were more marked in cells expressing the L isoform. ATRA treatment also led to
downregulation of bcl-2 and endogenous RAR in PML-RAR-expressing cells, but had little effect on the level of exogenously expressed PML-RAR. We conclude that (1) subtle differences exist in the biologic activities of the L and S isoforms of PML-RAR, and (2) both
isoforms are capable of transducing an ATRA-mediated signal that leads
to downregulation of bcl-2 and induction of programmed cell death.
Blood, Vol. 91 No. 9 (May 1), 1998:
pp. 3347-3356
© 1998 by The American Society of Hematology.
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