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Blood, 15 February 2002, Vol. 99, No. 4, pp. 1356-1363
NEOPLASIA
Frequent mutations in the ligand-binding domain of PML-RAR
after multiple relapses of acute promyelocytic leukemia: analysis for
functional relationship to response to all-trans
retinoic acid and histone deacetylase inhibitors in vitro and
in vivo
Da-Cheng Zhou,
Soon H. Kim,
Wei Ding,
Cynthia Schultz,
Raymond P. Warrell Jr, and
Robert E. Gallagher
From the Departments of Oncology and Pathology,
Montefiore Medical Center, Albert Einstein Cancer Center, Bronx, NY;
and the Developmental Chemotherapy and Leukemia Services, Department of
Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY.
This study identified missense mutations in the ligand binding
domain of the oncoprotein PML-RAR in 5 of 8 patients with acute
promyelocytic leukemia (APL) with 2 or more relapses and 2 or more
previous courses of all-trans retinoic acid
(RA)-containing therapy. Four mutations were novel (Lys207Asn,
Gly289Arg, Arg294Trp, and Pro407Ser), whereas one had been previously
identified (Arg272Gln; normal RAR1 codon assignment). Five patients
were treated with repeat RA plus phenylbutyrate (PB), a histone
deacetylase inhibitor, and one patient experienced a prolonged clinical
remission. Of the 5 RA + PB-treated patients, 4 had
PML-RAR mutations. The Gly289Arg mutation in the clinical responder
produced the most defective PML-RAR function in the presence of RA
with or without sodium butyrate (NaB) or trichostatin A. Relapse APL
cells from this patient failed to differentiate in response to RA but
partially differentiated in response to NaB alone, which was augmented
by RA. In contrast, NaB alone had no differentiation effect on APL cells from another mutant case (Pro407Ser) but enhanced differentiation induced by RA. These results indicate that PML-RAR mutations occurred with high frequency after multiple RA treatment relapses, indicate that the functional potential of PML-RAR was not correlated with clinical response to RA + PB treatment, and suggest that the
response to RA + PB therapy in one patient was related to the
ability of PB to circumvent the blocked RA-regulated gene response pathway.
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