Atypical mRNA fusions in PML-RARA positive, RARA-PML negative acute promyelocytic leukemia.
Reciprocal RARA-PML transcripts are not detected in approximately 25% of patients with PML-RARA positive acute promyelocytic leukemia (APL), but the reasons for this are poorly understood. We studied 21 PML-RARA positive/RARA-PML negative cases by bubble PCR and multiplex long template PCR to identify the genomic breakpoints. Additional RT-PCR analysis was performed based on the DNA findings. Three cases were found to have complex rearrangements involving a third locus: the first had a PML-CDC6-RARA forward DNA fusion and expressed a chimeric PML-CDC6-RARA mRNA in addition to a PML-RARA. The other two had HERC1-PML and NT_009714.17-PML genomic fusion sequences at their respective reciprocal breakpoints. Six patients were falsely classified as RARA-PML negative due to deletions on chromosome 15 and/or 17, or alternative splicing leading to atypical RARA-PML fusion transcripts, which were not identified by conventional RT-PCR assays. This study demonstrates that the frequency of RARA-PML expression has been underestimated and highlights remarkable complexity at chromosomal breakpoint regions in APL even in cases with an apparently simple balanced t(15;17)(q24;q12).
Pathologisches Institut, Universitätsmedizin Mannheim, Theodor-Kutzer-Ufer 1-3, Mannheim, Germany.
Christoph
C
Walz
David
D
Grimwade
Susanne
S
Saussele
Eva
E
Lengfelder
Claudia
C
Haferlach
Susanne
S
Schnittger
Marina
M
Lafage-Pochitaloff
Andreas
A
Hochhaus
Nicholas C P
NC
Cross
Andreas
A
Reiter
D000293:Adolescent; D000328:Adult; D000368:Aged; D017398:Alternative Splicing; D002874:Chromosome Mapping / Q000379:methods; D017353:Gene Deletion; D015321:Gene Rearrangement; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute / Q000235:genetics* / Q000378:metabolism; D008875:Middle Aged; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D015514:Oncogene Proteins, Fusion / Q000235:genetics* / Q000378:metabolism; D016133:Polymerase Chain Reaction / Q000379:methods; D000071156:Promyelocytic Leukemia Protein; D012333:RNA, Messenger / Q000235:genetics* / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism
D009687:Nuclear Proteins; D015514:Oncogene Proteins, Fusion; D000071156:Promyelocytic Leukemia Protein; D012333:RNA, Messenger; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; C093476:promyelocytic leukemia-retinoic acid receptor alpha fusion oncoprotein; C070576:PML protein, human