title: Frequent mutations in the ligand-binding domain of PML-RARalpha 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.
abstract: This study identified missense mutations in the ligand binding domain of the oncoprotein PML-RARalpha 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 RARalpha1 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-RARalpha mutations. The Gly289Arg mutation in the clinical responder produced the most defective PML-RARalpha 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-RARalpha mutations occurred with high frequency after multiple RA treatment relapses, indicate that the functional potential of PML-RARalpha 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.
authors.affiliation: Department of Oncology, Montefiore Medical Center, Albert Einstein Cancer Center, Bronx, NY 10467, USA.
authors.forename: Da-Cheng
authors.initials: DC
authors.lastname: Zhou
authors.forename: Soon H
authors.initials: SH
authors.lastname: Kim
authors.forename: Wei
authors.initials: W
authors.lastname: Ding
authors.forename: Cynthia
authors.initials: C
authors.lastname: Schultz
authors.forename: Raymond P
authors.initials: RP
authors.lastname: Warrell
authors.forename: Robert E
authors.initials: RE
authors.lastname: Gallagher
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000494:pharmacology; D001665:Binding Sites / Q000235:genetics; D002087:Butyrates / Q000008:administration & dosage / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects; D004252:DNA Mutational Analysis; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D006877:Hydroxamic Acids / Q000008:administration & dosage / Q000494:pharmacology; D015473:Leukemia, Promyelocytic, Acute / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D020125:Mutation, Missense; D009363:Neoplasm Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D015514:Oncogene Proteins, Fusion / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D010654:Phenylbutyrates / Q000008:administration & dosage / Q000494:pharmacology; D011379:Prognosis; D011485:Protein Binding; D012008:Recurrence; D015533:Transcriptional Activation / Q000187:drug effects; D016896:Treatment Outcome; D014212:Tretinoin / Q000008:administration & dosage* / Q000378:metabolism / Q000494:pharmacology
chemical_list: D002087:Butyrates; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D009363:Neoplasm Proteins; D015514:Oncogene Proteins, Fusion; D010654:Phenylbutyrates; C093476:promyelocytic leukemia-retinoic acid receptor alpha fusion oncoprotein; C012589:trichostatin A; D014212:Tretinoin