Atypical mRNA fusions in PML-RARA positive, RARA-PML negative acute promyelocytic leukemia

✍ Scribed by Christoph Walz; David Grimwade; Susanne Saussele; Eva Lengfelder; Claudia Haferlach; Susanne Schnittger; Marina Lafage-Pochitaloff; Andreas Hochhaus; Nicholas C. P. Cross; Andreas Reiter

• Publisher: John Wiley and Sons
• Year: 2010
• Tongue: English
• Weight: 251 KB
• Volume: 49
• Category: Article
• ISSN: 1045-2257
• DOI: 10.1002/gcc.20757

✦ Synopsis

Abstract

Reciprocal RARA‐PML transcripts are not detected in ∼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). © 2010 Wiley‐Liss, Inc.