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Prepublished online as a Blood First Edition Paper on June 7, 2002; DOI 10.1182/blood-2002-02-0614.
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Blood, 1 October 2002, Vol. 100, No. 7, pp. 2586-2596
NEOPLASIA
Response to histone deacetylase inhibition of novel PML/RAR
mutants detected in retinoic acid-resistant APL cells
Sylvie Côté,
Angelika Rosenauer,
Andrea Bianchini,
Karen Seiter,
Jonathan Vandewiele,
Clara Nervi, and
Wilson H. Miller Jr
From the Lady Davis Institute for Medical Research, Sir
Mortimer B. Davis Jewish General Hospital and McGill University
Department of Oncology and Medicine, Montreal, Quebec, Canada;
Dipartimento di Istologia ed Embriologia Medica, Università di
Roma "La Sapienza," Rome, Italy; and Department of
Medicine/Neoplastic Diseases, New York Medical College, Valhalla, NY.
Resistance to all-trans retinoic acid (ATRA)
remains a clinical problem in the treatment of acute promyelocytic
leukemia (APL) and provides a model for the development of novel
therapies. Molecular alterations in the ligand-binding domain (LBD) of
the PML/RAR fusion gene that characterizes APL
constitute one mechanism of acquired resistance to ATRA. We identified
missense mutations in PML/RAR from an additional
ATRA-resistant patient at relapse and in a novel ATRA-resistant cell
line, NB4-MRA1. These cause altered binding to ligand and
transcriptional coregulators, leading to a dominant-negative block of
transcription. These mutations are in regions of the LBD that appear to
be mutational hot spots occurring repeatedly in ATRA-resistant APL
patient cells. We evaluated whether histone deacetylase (HDAC)
inhibition could overcome the effects of these mutations on
ATRA-induced gene expression. Cotreatment with ATRA and TSA restored
RAR gene expression in NB4-MRA1 cells, whose PML/RAR
mutation is in helix 12 of the LBD, but not in an APL cell line
harboring the patient-derived PML/RAR mutation, which was between
helix 5 and 6. Furthermore, ATRA combined with TSA increases histone 4 acetylation on the RAR promoter only in NB4-MRA1 cells.
Consistent with these results, the combined treatment induces
differentiation of NB4-MRA1 only. Thus, the ability of an HDAC
inhibitor to restore ATRA sensitivity in resistant cells may depend on
their specific molecular defects. The variety of PML/RAR
mutations arising in ATRA-resistant patients begins to explain how APL
patients in relapse may differ in response to transcription therapy
with HDAC inhibitors.
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