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 language||English (US)|
|Number of pages||8|
|State||Published - Jan 1 1995|
ASJC Scopus subject areas
- Cell Biology