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Missense mutations in PML-RARA are critical for the lack of responsiveness to arsenic trioxide treatment.

Abstract
Arsenic trioxide (As₂O₃) is a highly effective treatment for patients with refractory/relapsed acute promyelocytic leukemia (APL), but resistance to As₂O₃ has recently been seen. In the present study, we report the findings that 2 of 15 patients with refractory/relapsed APL treated with As₂O₃ were clinically As₂O₃ resistant. Leukemia cells from these 2 patients harbored missense mutations in promyelocytic leukemia gene-retinoic acid receptor-α gene (PML-RARA) transcripts, resulting in amino acid substitutions of A216V and L218P in the PML B2 domain. When wild-type or mutated PML-RARA (PR-WT and PR-B/L-mut, respectively) were overexpressed in HeLa cells, immunoblotting showed SUMOylated and/or oligomerized protein bands in PR-WT but not in PR-B/L-mut after As₂O₃ treatment. Protein-localization analysis indicated that PR-WT in the soluble fraction was transferred to the insoluble fraction after treatment with As₂O₃, but PR-B/L-mut was stably detected in fractions both with and without As₂O₃. Immunofluorescent microscopy analysis showed PR-WT localization as a microgranular pattern in the cytoplasm without As₂O₃ and as a macrogranular pattern with As₂O₃. PR-B/L-mut was diffusely observed in the cytoplasm with and without As₂O₃. Nearly identical localization patterns were observed in patients' primary cells. Therefore, B2 domain mutations may play an important role in aberrant molecular responses toAs₂O₃ and may be critical for As₂O₃ resistance in APL.
AuthorsEmi Goto, Akihiro Tomita, Fumihiko Hayakawa, Akihide Atsumi, Hitoshi Kiyoi, Tomoki Naoe
JournalBlood (Blood) Vol. 118 Issue 6 Pg. 1600-9 (Aug 11 2011) ISSN: 1528-0020 [Electronic] United States
PMID21613260 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Antineoplastic Agents
  • Arsenicals
  • Nuclear Proteins
  • Oncogene Proteins, Fusion
  • Oxides
  • Receptors, Retinoic Acid
  • Transcription Factors
  • Tumor Suppressor Proteins
  • promyelocytic leukemia-retinoic acid receptor alpha fusion oncoprotein
  • retinoic acid receptor alpha
  • PML protein, human
  • arsenic trioxide
Topics
  • Adult
  • Antineoplastic Agents (pharmacology, therapeutic use)
  • Arsenicals (pharmacology, therapeutic use)
  • Binding Sites (genetics)
  • Cytoplasm (drug effects, metabolism)
  • Drug Resistance, Neoplasm (genetics)
  • Female
  • HeLa Cells
  • Humans
  • Immunoblotting
  • Leukemia, Promyelocytic, Acute (drug therapy, genetics, pathology)
  • Male
  • Microscopy, Fluorescence
  • Middle Aged
  • Mutation, Missense
  • Neoplasm Recurrence, Local (genetics)
  • Nuclear Proteins (genetics, metabolism)
  • Oncogene Proteins, Fusion (genetics, metabolism)
  • Oxides (pharmacology, therapeutic use)
  • Receptors, Retinoic Acid (genetics, metabolism)
  • Reverse Transcriptase Polymerase Chain Reaction
  • Sumoylation (drug effects)
  • Transcription Factors (genetics, metabolism)
  • Transcription, Genetic (drug effects)
  • Tumor Suppressor Proteins (genetics, metabolism)
  • U937 Cells
  • Young Adult

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