Frequency and spectrum of atypical BCR-ABL1 transcripts in chronic myeloid leukemia

Kearney L., Crampe M., Langabeer S.E.*

Submitted: August 06, 2019.
*Correspondence: E-mail: slangabeer@stjames.ie
Abbreviations used: CML — chronic myeloid leukemia; RT-PCR — reverse transcription polymerase chain reaction; TKI — tyrosine kinase inhibitor.

DOI: 10.32471/exp-oncology.2312-8852.vol-42-no-1.14300

The BCR-ABL1 oncogene is the molecular hallmark of chronic myeloid leukemia (CML) with the majority of patients possessing a fusion between BCR exon 13 or 14 and ABL1 exon a2 (e13a2 and e14a2 respectively). However, a minority of patients express atypical transcripts usually as due to splicing of alternative BCR or ABL1 exons. These variants become apparent upon discordant diagnostic cytogenetic and molecular testing and may be resolved by multiplex, reverse transcription polymerase chain reaction (RT-PCR) or sequencing approaches [1]. In a recent international survey of BCR-ABL1 transcript types in more than 34,000 CML patients, 1.93% of cases expressed these atypical forms [2]. It is therefore likely that any laboratory performing molecular dia­gnosis or monitoring of more than 50 CML patients will have encountered a variant BCR-ABL1 transcript. We sought to review the incidence and type of atypical BCR-ABL1 transcripts in CML patients from the National molecular dia­gnostic centre in order to inform appropriate dia­gnostic and monitoring techniques.

New or existing CML patients were identified from January 2005 to June to 2019 inclusive at the National center for the molecular diagnosis and monitoring of CML in Ireland. All patients had cytogenetic or fluorescence in situ hybridization confirmation of a t(9;22) translocation or BCR-ABL1 fusion signal respectively. BCR-ABL1 detection and quantitative RT-PCR were performed using standardized approaches throughout this period with Sanger sequencing used for confirmation of an atypical fusion transcript [3, 4]. Of 706 CML patients, atypical BCR-ABL1 transcripts were detected in 16 (2.3%). These variants comprised e1a2 (n = 4), e6a2 (n = 2), e8a1 (n = 1), e13a3 (n = 1), atypical e13a2 with a deletion and insertion (n = 2), and e19a2 (n = 6).

The above demonstrates that the frequency and spectrum of atypical BCR-ABL1 transcripts in the Irish CML population is similar to that seen elsewhere. The clinical importance of correct identification of the atypical BCR-ABL1 transcripts is two-fold. Firstly, there is accumulating evidence for a BCR-ABL1 genotype-tyrosine kinase inhibitor (TKI) response correlation: patients expressing the shorter transcript types such as e1a2 and e6a2 have an aggressive disease with higher rates of blast crisis transformation [5, 6] whereas TKI responses in patients with longer BCR-ABL1 trans­cript types such as the e19a2 are generally favorable [7, 8]: establishing the transcript type will therefore inform selection of TKI. Secondly, monitoring the molecular response by quantitation of BCR-ABL1 transcripts is now an integral part of CML patient management with significant advances made towards harmonization of diffe­rent methodological approaches: characterization of a variant transcript type therefore allows selection of correct primers and probes for quantitative RT-PCR. However, to date, quantitation of atypical BCR-ABL1 transcript has only been performed on an ad hoc basis [9]. Given that the survival of CML patients receiving TKI therapy is similar to that of the normal population, more patients with these atypical BCR-ABL1 transcripts will require monitoring. Furthermore, given the possibility for treatment-free remission in which important criteria for TKI discontinuation are the length and depth of molecular remission, consensus standards and methodologies are now required for this small but expanding population of CML patients.

CONFLICTS OF INTEREST

The authors declare no competing financial inte­rests.

REFERENCES

  • 1. Burmeister T, Reinhardt R. A multiplex PCR for improved detection of typical and atypical BCR-ABL fusion transcripts. Leuk Res 2008; 32: 579–85.
  • 2. Baccarani M, Castagnetti F, Gugliotta G, et al. The proportion of different BCR-ABL1 transcript types in chronic myeloid leukemia. An international overview. Leukemia 2019; 33: 1173–83.
  • 3. Van Dongen JJ, Macintyre EA, Gabert JA, et al. Standardized RT-PCR analysis of fusion gene transcripts from chromosome aberrations in acute leukemia for detection of minimal residual disease. Report of the BIOMED-1 Concerted Action: investigation of minimal residual disease in acute leukemia. Leukemia 1999; 13: 1901–28.
  • 4. Gabert J, Beillard E, van der Velden VH, et al. Standardization and quality control studies of “real-time” quantitative reverse transcriptase polymerase chain reaction of fusion gene transcripts for residual disease detection in leukemia — a Europe Against Cancer program. Leukemia 2003; 17: 2318–57.
  • 5. Gong Z, Medeiros LJ, Cortes JE, et al. Clinical and prognostic significance of e1a2 BCR-ABL1 transcript subtype in chronic myeloid leukemia. Blood Cancer J 2017; 7: e583.
  • 6. Beel KA, Lemmens J, Vranckx H, et al. CML with e6a2 BCR-ABL1 transcript: an aggressive entity? Ann Hematol 2011; 90: 1241–3.
  • 7. Arun AK, Senthamizhselvi A, Mani S, et al. Frequency of rare BCR-ABL1 fusion transcripts in chronic myeloid leukemia patients. Int J Lab Hematol 2017; 39: 235–42.
  • 8. Qin YZ, Jiang Q, Jiang H, et al. Prevalence and outcomes of uncommon BCR-ABL1 fusion transcripts in patients with chronic myeloid leukaemia: data from a single centre. Br J Haematol 2018; 182: 693–700.
  • 9. Langabeer SE. Standardized molecular monitoring for variant BCR-ABL1 transcripts in chronic myeloid leukemia. Arch Pathol Lab Med 2015; 139: 969.
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