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Identification of a rare e8a2 BCR-ABL fusion gene in three novel chronic myeloid leukemia patients treated with imatinib

Leukemia volume 19, pages 2334–2336 (2005)Cite this article

TO THE EDITOR

These cases (patients no. 1, 2 and 3) were diagnosed with CML in chronic phase based on typical peripheral blood findings and on standard karyotyping analyses indicating t(9;22)(q34;q11). The relevant clinical and biological data for the patients are given in Table 1. In case no. 1, fluorescence in situ hybridization (FISH) analysis performed with dual color probes for BCR and ABL genes (LSI bcr/abl ES Dual Color Translocation Probe, VYSIS Downer's Grove, IL, USA) showed a typical M-BCR picture in 20 metaphases and 100 interphase nuclei (data not shown) which was different from the case previously described.2 The first case (no. 1), a 40-year-old male patient, was referred to the Centre Hospitalier Lyon Sud hospital in July 2002 for hyperleukocytosis at 39 × 109/l with myelemia, discovered on a systematic peripheral blood analysis. After karyotyping analysis, imatinib was introduced in August 2002. The cases no. 2 and no. 3 were referred to the Saint Louis hospital in February 2002 and November 2002, and imatinib was introduced in March and December 2002, respectively. In all cases, multiplex RT-PCR performed for BCR-ABL at diagnosis showed an atypically large fragment that turned out to correspond, after direct sequencing, to an e8a2 fusion transcript with a 55 base pair (bp) insert that wholly matched an inverted sequence from ABL intron Ib (Figure 1a). The monitoring of the minimal residual disease (MRD) was carried out using real-time RT-PCR3 with specific forward primers, located close to the e8-BCR (Figure 1b). The introduction of imatinib mesylate therapy at 400 mg/day allowed complete hematologic and cytogenetic responses at 6 months and a major molecular response in all cases, with a reduction of at least three logs of BCR-ABL transcript levels compared to the diagnosis, at a median follow-up of 34 months (range 30–39) (Figure 1b). Of note, in cases no. 2 and no. 3, a major molecular response was obtained only after increasing the dosage of imatinib, suggesting that those patients may require higher doses (600 mg/day) of imatinib to achieve proper molecular response. Most of the previously described patients with an e8a2 BCR-ABL fusion transcript had thrombocytosis and seemed to be associated with worse prognosis.2 None of the cases described here showed thrombocytosis (Table 1). Moreover, none of the patients previously described, treated with interferon-α, achieved even a minor response; all of the cases treated with imatinib were alive at a median follow-up of 34 months, achieved complete cytogenetic remission at a median follow-up of 7 months and a major molecular remission (BCR-ABL/ABL<0,12%) at a median follow-up of 20 months indicating thus the efficacy of imatinib mesylate in patients with rare BCR-ABL transcripts. The aggressive clinical course of these leukemias suggested previously could be shrouded by appropriate targeted therapy. The direct junction between exons e8 from BCR gene and a2 from ABL gene would generate a stop codon. The open reading frame was preserved either by insertion of intronic sequences from ABL gene, or either (in 3/11 cases described previously) with a break inside the exon e8 from BCR gene.2 An interesting common feature was that in all cases described here (and in three previously reported patients,2, 4, 5 which accounts for more than 50% of the e8a2 patients described to date and therefore could represent the most frequent rearrangement in e8a2 patients) molecular study showed an identical 55 bp inverted fragment insertion from ABL intron Ib (Figure 1a). It has been suggested that the presence of translisin recognition sites, ALU sequences or cryptic splice site signals in the translocation region could contribute to these complex rearrangements.5, 6, 7 This 55 bp inverted fragment added to the two first nucleotides of exon a2 from ABL gene is capable of encoding 19 amino acids. Protein motif analysis using the PROSITE database indicated that they contain a Clathrin box motif, found on cargo adaptator proteins (amino acids 14–18, Figure 1a). There is little information about the biological function of this protein feature, but it could be involved in endocytosis or in cooperative interaction between proteins in vesicular trafficking.8 Obviously, structure/function studies would bring a more comprehensive survey on the real biological significance of this small motif insertion.

Table 1 Clinical and molecular characteristics of CML patients with e8a2 rearrangement
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Acknowledgements

This work was supported by the Hospices Civils de Lyon, Ligue contre le cancer du Rhône (to SH, FEN, KC) and a grant from Cancéropôle Lyon Auvergne Rhône-Alpes (CLARA) 2003 (to SH, FEN). We thank Annick Bertholin for technical assistance.

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Authors and Affiliations

  1. Laboratoire Central d'Hématologie, Hôpital Saint-Louis, Paris, France

    J M Cayuela & M H Bui-Thi

  2. Centre d'investigation Clinique, Hôpital Saint Louis, Paris, France

    P Rousselot

  3. Service d'Hématologie, Hôpital Mignot, Versailles, France

    P Rousselot

  4. Service d'Hématologie Clinique, Hôpital Ed Herriot, Lyon, France

    F Nicolini

  5. Service d'Hématologie, Centre Hospitalier Lyon Sud, Pierre-Benite, France

    D Espinouse

  6. Laboratoire d’hématologie et de cytogénétique, Centre Hospitalier Lyon Sud, Pierre-Benite, France

    C Ollagnier, K Chabane, E Callet-Bauchu, I Tigaud, J P Magaud & S Hayette

  7. Service Clinique des maladies du sang, Hôpital Saint-Louis, Paris, France

    E Raffoux

  8. EA3737, Université Claude Bernard, Pierre-Bénite, France

    E Callet-Bauchu, I Tigaud, J P Magaud & S Hayette

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Correspondence to S Hayette.

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Cayuela, J., Rousselot, P., Nicolini, F. et al. Identification of a rare e8a2 BCR-ABL fusion gene in three novel chronic myeloid leukemia patients treated with imatinib. Leukemia 19, 2334–2336 (2005). https://doi.org/10.1038/sj.leu.2403986

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