Characterization of a novel variant BCR–ABL1 fusion transcript in a patient with chronic myeloid leukemia

Abstract

Molecular monitoring of BCR-ABL1 transcript levels using quantitative polymerase chain reaction is an essential part of the modern management of chronic myeloid leukemia patients treated with tyrosine kinase inhibitors. Establishing the diagnostic BCR-ABL1 fusion transcript is necessary in order to select appropriate primers and probes for such monitoring. A case is described in which quantitative polymerase chain reaction failed to detect the presence of BCR-ABL1 fusion transcript in a Philadelphia chromosome-positive chronic myeloid leukemia patient. Further investigation demonstrated a novel in-frame BCR-ABL1 fusion transcript with a breakpoint in BCR exon 13 and insertion of a sequence of ABL1 intron 1, therefore enabling subsequent molecular monitoring. This case highlights the requirement for characterization of the BCR-ABL1 transcript type at chronic myeloid leukemia diagnosis. Issues concerning standardized methodological approaches and interpretation of transcript levels in such rare cases are discussed.

Chronic Myeloid Leukemia, Version 2.2021, NCCN Clinical Practice Guidelines in Oncology

“…Qualitative RT-PCR, nested RT-PCR, or Sanger sequencing are useful for the identification of atypical BCR-ABL1 transcripts. 28,29 qPCR using log-reduction from standardized baseline can be used to monitor e1a2 transcripts, and monitoring e19a2 transcripts is usually performed using qualitative RT-PCR or nested RT-PCR. However, there are no standardized qPCR assays for monitoring molecular response to TKI therapy in patients with atypical BCR-ABL1 transcripts.…”

Guidelines for the treatment of chronic myeloid leukemia from the NCCN and ELN: differences and similarities

“…Qualitative RT-PCR, nested RT-PCR, or Sanger sequencing are convenient techniques for the identification of atypical BCR::ABL1 transcripts [25,26]. NCCN states that qPCR using standardized baseline log-reduction may be used to monitor e1a2 transcripts, and qualitative RT-PCR or nested RT may be feasible for monitoring e19a2 transcripts.…”

BCR-ABL Positive Childhood Chronic Myeloid Leukemia

“…For us the clinical significance of using this technique was to explore the option of using molecular targeted therapy as treatment modality given that the potential curative treatment hemopoietic stem cell transplantation (HSCT) is presently not available in our centre. The use of this molecular diagnostic technique (PCR) is now considered an essential part of modern management of CML patients especially in patients whose bone marrow karyotype did not demonstrate the Ph chromosome [8].…”