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

Robert E. Gallagher, Yun Ping Li, Sreenivas Rao, Elisabeth M. Paietta, Janet Andersen, Polly Etkind, John M. Bennett, Martin S. Tallman, Peter H. Wiernik

Research output: Contribution to journalArticle

85 Citations (Scopus)

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 at 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 juction 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
StatePublished - Aug 15 1995

Fingerprint

Acute Promyelocytic Leukemia
Tretinoin
L Forms
Exons
Fusion reactions
Nucleotides
Genes
Introns
Messenger RNA
Reverse Transcriptase Polymerase Chain Reaction
Open Reading Frames
Polymerase chain reaction
RNA-Directed DNA Polymerase
Reaction products
In Vitro Techniques

ASJC Scopus subject areas

  • Hematology

Cite this

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. / Gallagher, Robert E.; Li, Yun Ping; Rao, Sreenivas; Paietta, Elisabeth M.; Andersen, Janet; Etkind, Polly; Bennett, John M.; Tallman, Martin S.; Wiernik, Peter H.

In: Blood, Vol. 86, No. 4, 15.08.1995, p. 1540-1547.

Research output: Contribution to journalArticle

Gallagher, Robert E. ; Li, Yun Ping ; Rao, Sreenivas ; Paietta, Elisabeth M. ; Andersen, Janet ; Etkind, Polly ; Bennett, John M. ; Tallman, Martin S. ; Wiernik, Peter H. / 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. In: Blood. 1995 ; Vol. 86, No. 4. pp. 1540-1547.
@article{efc1071fec194691ba27d8db278cc766,
title = "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",
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 at 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 juction 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.",
author = "Gallagher, {Robert E.} and Li, {Yun Ping} and Sreenivas Rao and Paietta, {Elisabeth M.} and Janet Andersen and Polly Etkind and Bennett, {John M.} and Tallman, {Martin S.} and Wiernik, {Peter H.}",
year = "1995",
month = "8",
day = "15",
language = "English (US)",
volume = "86",
pages = "1540--1547",
journal = "Blood",
issn = "0006-4971",
publisher = "American Society of Hematology",
number = "4",

}

TY - JOUR

T1 - Characterization of Acute Promyelocytic Leukemia Cases with PML-RARα Break/Fusion Sites in PML Exon 6

T2 - Identification of a Subgroup with Decreased in Vitro Responsiveness to All-Trans Retinoic Acid

AU - Gallagher, Robert E.

AU - Li, Yun Ping

AU - Rao, Sreenivas

AU - Paietta, Elisabeth M.

AU - Andersen, Janet

AU - Etkind, Polly

AU - Bennett, John M.

AU - Tallman, Martin S.

AU - Wiernik, Peter H.

PY - 1995/8/15

Y1 - 1995/8/15

N2 - 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 at 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 juction 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.

AB - 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 at 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 juction 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.

UR - http://www.scopus.com/inward/record.url?scp=0029162610&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0029162610&partnerID=8YFLogxK

M3 - Article

VL - 86

SP - 1540

EP - 1547

JO - Blood

JF - Blood

SN - 0006-4971

IS - 4

ER -