A Rare e14a3 (b3a3) BCR-ABL Fusion Transcript in Chronic Myeloid Leukemia

Abstract

Chronic myelogenous leukemia (CML) is the first human cancer causally linked to a specific chromosomal abnormality, the Philadelphia chromosome (Ph), which is a product of a reciprocal translocation between chromosome 9 and 22 [t(9;22)(q34;q11.2)]. This particular translocation results in the BCR-ABL gene fusion that was subsequently shown to have transforming activity due to the deregulated tyrosine kinase activity of ABL.1 In CML, Ͼ95% of the breakpoints involve the M-bcr region consisting of BCR introns downstream of either exon 13 (e13, previously known as b2) or 14 (e14, previously known as b3) and introns upstream of ABL exon 2 (a2). These BCR-ABL e13a2 and e14a2 fusions result in a 210-kd fusion protein.2 There are two less common breakpoints in the intronic region between the alternative BCR exon 2 known as m-bcr, and between BCR exons 19 and 20, known as -bcr, which encode a 190-kd (e1a2) and 230-kd fusion protein (e19a2), respectively.3,4 Rare atypical breakpoints have also been sporadically reported and can be grouped into four categories: BCR breakpoints originating within introns that lie outside M-bcr, m-bcr, or -bcr fused to ABL a2; BCR breakpoints occurring within exons fused to ABL a2; typical BCR breakpoints (M-bcr, m-bcr, or -bcr) fused to ABL breakpoints located downstream of a2; and transcripts containing intervening sequences between BCR and ABL a2. There are multiple methods for detecting the BCR-ABL translocation including cytogenetics, Southern blot, fluorescence in situ hybridization (FISH), and reverse transcription polymerase chain reaction (RT-PCR) (including quantitative qRT-PCR). Each method has advantages and disadvantages. Cytogenetics, Southern blot, and some FISH-based assays should be able to detect essentially all BCR-ABL translocations regardless of the breakpoints, while RT-PCR assays are limited in the breakpoints detected based on the location of the primers and probes. However, cytogenetics, Southern blot, and FISH all have limits of detection of approximately

Frequency of rare BCR‐ABL1 fusion transcripts in chronic myeloid leukemia patients

“…BCR‐ABL1 fusion transcripts with intronic breakpoints downstream of ABL1 a2 (e13a3, e14a3) are exceptionally rare with very few such cases reported till date, and the prognosis of patients with these transcripts is controversial . Melo J et al .…”

How to detect the rare BCR‑ABL (e14a3) transcript: A case report and literature review

“…The patient in the present study also appeared to have a good response to imatinib. Combining these data with previous studies (5,10,16), patients with the BCR-ABL e14a3 transcript may expect a good clinical course.…”

“…In addition, these 14 patients exhibited a less aggressive form of the disease and lower WBC counts, ranging from 9-300x10 9 /l. It was also noted that the deletion of exon2 did not affect the curative effects of imatinib, and 7 patients appeared to respond well to treatment with this drug (5,10). The patient in the present study also appeared to have a good response to imatinib.…”

Complete cytogenetic response to Nilotinib in a chronic myeloid leukemia case with a rare e13a3(b2a3) BCR-ABL fusion transcript: A case report

“…The BCR-ABL a3 breakpoint does not alter the sequence coding for the ATP/imatinib binding domain, but alterations in tertiary structure compared with a typical a2 fusion could affect drug response. The clinical outcomes specific to CML patients with BCR-ABL a3 fusions are difficult to define due to the limited number of cases reported (2,4).…”