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Blood, 1 August 2002, Vol. 100, No. 3, pp. 1008-1013
NEOPLASIA
Targeted removal of PML-RAR protein is required prior to
inhibition of histone deacetylase for overcoming
all-trans retinoic acid differentiation resistance in
acute promyelocytic leukemia
Yongkui Jing,
Lijuan Xia, and
Samuel Waxman
From the Division of Medical Oncology, Department of
Medicine, Mount Sinai School of Medicine, New York, NY.
All-trans retinoic acid (tRA)-induced differentiation
in NB4 cells, a cell line derived from an acute promyelocytic leukemia patient with t(15;17) translocation, is markedly facilitated by sodium
butyrate (NaB), a histone deacetylase inhibitor (HDACI), or by
hexamethylene bisacetamide (HMBA), a non-HDACI
tRA-differentiation inducer, as determined by nitroblue
tetrazolium reduction. The tRA-induced expression of
RIG-G, Bfl-1/A1, and p21waf1 and, to a lesser extent,
of CCAAT/enhancer binding protein- (C/EBP) are also
enhanced by such combined treatments. Both responses are
associated with a facilitated diminution of the leukemogenic PML-RAR
protein and retained  PML-RAR, a cleavage product. Treatment with
tRA in tRA differentiation-resistant NB4 subclones R4 and MR-2 does
not result in PML-RAR diminution and the tested gene expressions.
Moreover, the addition of HMBA or NaB with tRA results in only minimal
increase of differentiation in the tRA differentiation-resistant subclones. The increases in acetylated histone H3 (AcH3) and AcH4 in
NaB-treated NB4, R4, and MR-2 cells are similar and do not correlate
with the extent of differentiation induction when NaB and HMBA are
given in combination with tRA. Arsenic trioxide
(As2O3) treatment results in the total
degradation of PML-RAR without increasing AcH3 or AcH4 or inducing
differentiation in R4 cells. As2O3 in
combination with tRA induces gene (Bfl-1/A1 and C/EBP) expression
and partial differentiation. Both NaB and HMBA addition to
As2O3-plus-tRA-treated R4 cells further
enhances differentiation. These results suggest that elimination of the
dominant negative PML-RAR protein is required prior to inhibition of
histone deacetylase to fully overcome tRA-differentiation resistance in
APL cells.
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