Characterization of acute promyelocytic leukemia cases with PML-RARα break/fusion sites in PML exon 6: Identification of a subgroup with decreased in vitro responsiveness to all-trans retinoic acid

R. E. Gallagher, Y. P. Li, S. Rao, E. Paietta, J. Andersen, P. Etkind, J. M. Bennett, M. S. Tallman, P. H. Wiernik

Research output: Contribution to journalArticlepeer-review

88 Scopus citations

Abstract

Of 113 acute promyelocytic leukemia cases documented to have diagnostic PML-RARα hybrid mRNA, 10 cases (8.8%) had fusion sites in PML gene exon 6 (V-forms) rather than in the two common hybrid mRNA configurations resulting from breaksites in either PML gene intron 6 (L-forms) or intron 3 (S-forms). In 4 V-form cases, a common break/fusion site was discovered et PML gene nucleotide (nt) 1685, abutting a 3' cryptic splice donor sequence. The fusion site was proximal to the common site in 1 case and more distal in 5 cases. The open reading frame encoding a PML-RARα gene was consistently preserved, either by an in-frame fusion site or by the insertion of 3 to 127 unidentified nts. In 2 V-form cases, hybridization analysis of the reverse transcriptase-polymerase chain reaction products with a PML-RARα junction probe was required for discrimination from L-form cases. Two V-form subgroups were defined by in vitro sensitivity to all-trans retinoic acid (tRA)- induced differentiation: 4 of 4 cases tested with fusion sites at or 5' to nt 1685 (subgroup E6S) had reduced sensitivity (EC50 ≥ 10-7 mol/L), whereas 4 of 4 cases with fusion sites at or 3' to nt 1709 (subgroup E6L) had high sensitivity (EC50 < 10-8 mol/L) indistinguishable from that of L-form and S-form cases. These results provide the first link between PML-RARα configuration and tRA sensitivity in vitro and support the importance of subclassifying APL cases according to PML-RARα transcript type.

Original languageEnglish (US)
Pages (from-to)1540-1547
Number of pages8
JournalBlood
Volume86
Issue number4
DOIs
StatePublished - 1995

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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