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

Christoph Walz1, David Grimwade, Susanne Saussele

  • 1Pathologisches Institut, Universitätsmedizin Mannheim, Theodor-Kutzer-Ufer 1-3, Mannheim, Germany.

Genes, Chromosomes & Cancer
|February 16, 2010
PubMed

Insights

Many acute promyelocytic leukemia (APL) patients with PML-RARA fusion lack reciprocal RARA-PML transcripts due to complex rearrangements or alternative splicing, not just absence of the fusion. This study reveals underestimation of RARA-PML expression in APL.

Area of Science:

  • Hematology
  • Molecular Biology
  • Genetics

Background:

  • Approximately 25% of acute promyelocytic leukemia (APL) patients with PML-RARA fusion transcripts do not show reciprocal RARA-PML transcripts.
  • The underlying reasons for this discrepancy in RARA-PML transcript detection remain poorly understood.

Purpose of the Study:

  • To investigate the molecular mechanisms behind the absence of reciprocal RARA-PML transcripts in a subset of PML-RARA positive APL cases.
  • To identify genomic breakpoints and characterize complex rearrangements or alternative splicing events in these cases.

Main Methods:

  • Bubble PCR and multiplex long-template PCR were employed to identify genomic breakpoints in 21 PML-RARA positive/RARA-PML negative APL cases.
  • RT-PCR analysis was conducted based on the identified DNA findings to detect transcript fusions.

Main Results:

  • Three cases exhibited complex rearrangements involving a third locus, including a PML-CDC6-RARA fusion transcript alongside PML-RARA.
  • Two cases presented HERC1-PML and NT_009714.17-PML genomic fusions at reciprocal breakpoints.
  • Six patients were misclassified as RARA-PML negative due to chromosomal deletions or atypical RARA-PML transcripts missed by conventional RT-PCR.

Conclusions:

  • The frequency of RARA-PML expression in APL has likely been underestimated.
  • APL cases with apparently balanced t(15;17) can harbor significant complexity at chromosomal breakpoint regions.

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