CHARACTERIZATION OF ACUTE PROMYELOCYTIC LEUKEMIA CASES WITH PML-RAR-ALPHA BREAK FUSION SITES IN PML EXON-6 - IDENTIFICATION OF A SUBGROUP WITH DECREASED IN-VITRO RESPONSIVENESS TO ALL-TRANS-RETINOIC ACID
Re. Gallagher et al., CHARACTERIZATION OF ACUTE PROMYELOCYTIC LEUKEMIA CASES WITH PML-RAR-ALPHA BREAK FUSION SITES IN PML EXON-6 - IDENTIFICATION OF A SUBGROUP WITH DECREASED IN-VITRO RESPONSIVENESS TO ALL-TRANS-RETINOIC ACID, Blood, 86(4), 1995, pp. 1540-1547
Of 113 acute promyelocytic leukemia cases documented to have diagnosti
c PML-RAR alpha hybrid mRNA. 10 cases (8.8%) had fusion sites in PML g
ene exon 6 (V-forms) rather than in the two common hybrid mRNA configu
rations 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 at PML gene nucleotide (nt) 1685, abutting a 3' crypti
c splice donor sequence. The fusion site was proximal to the common si
te in 1 case and more distal in 5 cases. The open reading frame encodi
ng a PML-RAR alpha gene was consistently preserved, either by an in-fr
ame fusion site or by the insertion of 3 to 127 unidentified nts. In 2
V-form cases, hybridization analysis of the reverse transcriptase-pol
ymerase chain reaction products with a PML-RAR alpha juction probe was
required for discrimination from L-form cases. Two V-form subgroups w
ere defined by in vitro sensitivity to all-trans retinoic acid (tRA)-i
nduced differentiation: 4 of 4 cases tested with fusion sites at or 5'
to nt 1685 (subgroup E6S) had reduced sensitivity (EC(50) greater tha
n or equal to 10(-7) mol/L), whereas 4 of 4 cases with fusion sites at
or 3' to nt 1709 (subgroup E6L) had high sensitivity (EC(50) < 10(-8)
mol/L) indistinguishable from that of L-form and S-form cases. These
results provide the first link between PML-RAR alpha configuration and
tRA sensitivity in vitro and support the importance of subclassifying
APL cases according to PML-RAR alpha transcript type. (C) 1995 by The
American Society of Hematology.