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

Walz, Christopher, Grimwade, David, Saussele, Susanne, Lengfelder, Eva, Haferlach, Claudia, Schnittger, Susanne, Lafage-Pochitaloff, Marina, Hochhaus, Andreas, Cross, Nicholas C.P. and Reiter, Andreas (2010) Atypical mRNA fusions in PML-RARA positive, RARA-PML negative acute promyelocytic leukemia. Genes, Chromosomes and Cancer, 49 (5), 471-479. (doi:10.1002/gcc.20757).

Abstract

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)

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Contributors

Author: Nicholas C.P. Cross

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