Chronic Myeloid Leukemia With Rare Variant b2a3 (e13a3) BCR-ABL1 Fusion

Dear Editor, CML is characterized by reciprocal t(9;22)(q34;q11) translocation, which generates the BCR/ABL1 protein; that protein plays a critical role in the pathogenesis of CML. CML patients commonly harbor BCR-ABL1 fusion transcripts of types b3a2 (e14a2) or b2a2 (e13a2), while types e1a2 or e19a2 are less common. CML cases with b2a3-type fusion, in which the ABL1 exon 3 (a3) rather than exon 2 (a2) is fused to BCR, are rare. To date, only eight CML cases with solely b2a3-type fusion have been reported [1-6]. Here, we report a CML case with this rare b2a3-type BCR-ABL1 fusion and review the literature. A 57-yr-old man with marked leukocytosis was referred to a tertiary-care hospital and diagnosed as having CML in the chronic phase. Peripheral blood analysis showed a white blood cell (WBC) count of 384.7×10/L with 1% blasts, as well as a hemoglobin concentration of 7.3 g/dL, and a platelet count of 424×10/L. The bone marrow aspirate revealed a hypercellular marrow with left-shifted myeloid series and an increased number of megakaryocytes, with the occasional dwarf form. Gbanded karyotyping of the bone marrow cells demonstrated t(9;22)(q34;q11.2) in all of the 17 metaphase cells analyzed. A BCR/ABL1 gene rearrangement test by using reverse transcription PCR (RT-PCR) with home-brewed primers complementary to the ABL1 exon 2 (a2) failed to detect the BCR-ABL1 fusion transcript (reference sequence: BCR, NM_004327.3; ABL1, NM_005157.5). Negative results were also obtained with quantitative real-time RT-PCR analysis using the ipsogen BCR-ABL1 Mbcr IS-MMR Kit (Qiagen, Hilden, Germany). However, multiplex RT-PCR using the HemaVision kit (DNA Technology, Aarhus, Denmark) showed an atypical band of approximately 220 base pairs, suggesting the presence of the b2a3-type BCRABL1 fusion transcript (Fig. 1A). Sanger sequencing of the RTPCR product revealed fusion between the BCR exon 13 (b2) and the ABL1 exon 3 (a3) (Fig. 1B). The patient was started on nilotinib, which has been continued to the present. The clinical significance of b2a3-type fusion in CML has not been determined owing to its rarity. Therefore, we reviewed the literature for CML cases with this type of fusion in order to understand its clinical characteristics (Table 1). Cases with concomitant expression of another type of fusion transcript were eliminated to exclude the clinical effect of the other fusion transcript. All the eight patients underwent favorable clinical courses; none progressed to the transformed stages of accelerated or blast phases during the follow-up period. Additionally,