Imatinib Mesylate Resistance in a Chronic Myeloid Leukemia Patient with a Novel e8a2 BCR-ABL Transcript Variant

Abstract

Background: The vast majority of chronic myeloid leukemia (CML) patients express the BCR-ABL transcript with the b2a2 (e13a2) and/or b3a2 (e14a2) junctions. However, some rare cases have atypical breakpoints. Methods and Results: We identified a CML patient with a unique e8a2 BCR-ABL transcript variant. It contained the first 114 nucleotides of BCR exon 8, with an insertion of 16 nucleotides from the 3′ end of ABL intron 1a, followed by ABL exon 2. Due to her uncontrolled thrombocytosis after 3 years of interferon-α treatment, the patient received imatinib at a dosage of 400 mg/day. Though achieving a sustained and complete hematological response after 3 months, she was resistant to imatinib during the entire 65-month imatinib treatment. That is, she failed to achieve major cytogenetic response and there was no significant decrease in her BCR-ABL transcript levels. Meanwhile, an M351T mutant was detected at 18 months after the start of imatinib treatment. Conclusion: ABL point mutation is also a mechanism of imatinib resistance for CML patients with the BCR-ABL transcript variant.

Comprehensive Characterization of a Novel Intronic Pseudo-Exon Inserted within an e14/a2 BCR-ABL Rearrangement in a Patient with Chronic Myeloid Leukemia

“…To restore an artificial reading frame between BCR and ABL sequences, two mechanisms were mainly described: i) an intronic insertion of 3n ϩ 1 nucleotides between BCR exon e8 and ABL exon a2, 10,14 or ii) an intronic insertion within exon 8 (formation of an e8 partial/insertion/a2 rearrangement). [11][12][13] Concerning the e8/a2 rearrangement, the same ABL intron Ib inverted insertion has been reported in two CML cases. 10,18 From a technical standpoint, the very low incidence of small sequences inserted within typical e13/a2 or e14/a2 rearrangement in CML could be the consequence of a misidentification of these types of transcript in agarose gel electrophoresis (because of a too small difference in size).…”

“…In most of the cases, the inserted intronic sequence derived from ABL intron Ib (120.1 kb), [7][8][9][10][11] from ABL intron Ia (18.5 kb), 12,13 and more rarely from BCR intron 8 (10.2 kb).…”

Molecular characterization and follow‐up of five CML patients with new BCR–ABL1 fusion transcripts

“…The open reading frame is restored here by the insertion of a sequence being a multiple of 3 bp plus one additional bp (e.g., 111 + 1 bp or 153 + 1 bp), and therefore can produce an oncogenic protein. Several studies identified unusual e8‐[ins]‐a2 transcripts, with various junction types between BCR exon 8 and ABL1 exon 2, most being a 14–55 nucleotide insertion from ABL1 intron 1b (How et al, ; Branford et al, ; Sugimoto et al, ; Cayuela et al, ; Demehri et al, ; Tchirkov et al, ; Park et al, ; Qin et al, ). To our knowledge, only three cases involving a third partner gene have been identified to date (Demehri et al, ; McCarron et al, ; Frederick et al, ).…”

“…However, in fewer than 5% of cases, the junction between BCR and ABL1 is unusual, with a breakpoint outside the major BCR (M-BCR) region or with another exon than ABL1 exon 2. Thus, several other fusion transcripts have been identified to date involving breakpoints within exons (Hochhaus et al, 1996;How et al, 1999;Moreno et al, 2001;Demehri et al, 2005;Dessars et al, 2006;van der Velden et al, 2007) or a fragment insertion from an ABL1 intron (Ia or Ib) between BCR exon 8 and ABL1 exon 2 (Branford et al, 2000;Sugimoto et al, 2004;Cayuela et al, 2005;Demehri et al, 2005;Dessars et al, 2006;Park et al, 2008;Qin et al, 2008;Sadia et al, 2010). The majority of these atypical transcripts encode fusion proteins that lack or retain different BCR domains, which could influence the clinical phenotype of the disease.…”