Identification of a Rare e8a2 BCR-ABL Fusion Gene in Three Novel Chronic Myeloid Leukemia Patients Treated with Imatinib.
Authors: Cayuela Jean-Michel , Rousselot Philippe , Nicolini Franck , Espinouse Daniel , Ollagnier Christophe , Bui-Thi M.H. , Chabane Kaddour , Raffoux E. , Tigaud Isabelle , Magaud Jean-Pierre , Hayette Sandrine 
Published: April 2020

Abstract
Most patients with chronic myeloid leukemia (CML) express the BCR-ABL transcript with the b2a2 (e13a2) or b3a2 (e14a2) junctions corresponding to the major BCR gene breakpoint cluster region (M-BCR). We and others have reported that a small proportion of CML patients (1–2%), which have breakpoints that fall outside of the M-BCR, giving rise to shortened BCR-ABL transcripts (m-BCR, e6a2, b2a3, b3a3) or longer BCR-ABL transcripts (μ-BCR). The clinical and hematologic features of 8 additional patients with e8a2 BCR-ABL fusions transcripts have been recently reviewed (Demehri et al, Leukemia 2005) and, according to the authors, could be associated with thrombocytosis and a worse prognosis than common M-BCR transcripts. Here, we report three additional CML patients with an e8a2 BCR-ABL fusion transcript treated with imatinib and who achieved hematologic, cytogenetic remission. Molecular studies allowed us to quantify this rare BCR-ABL fusion mRNA. All the patients showed a major molecular response with a reduction of at least 3 logs compared to initial samples at a median follow-up of 34 months (range 30–39). None of the cases (patients #1, 2 and 3) described here showed thrombocytosis at diagnosis. The diagnosis of chronic phase CML was based on typical peripheral blood findings and cytogenetics. In all cases, standard karyotyping demonstrated a t(9;22)(q34;q11), but further molecular analysis revealed an atypical e8a2 BCR-ABL fusion gene. In case #1, FISH using the LSI-bcr/abl ES probe (Vysis) showed a typical M-BCR picture which was different with the case previously described. Multiplex RT-PCR for BCR-ABL and sequencing showed a fusion between BCR exon e8 and ABL exon a2, with a 55 base pair (bp) insert, which perfectly matched an inverted sequence from ABL intron Ib. Most of the patients with an e8a2 BCR-ABL fusion transcript previously described seem to be associated with a worse prognosis because none of them treated with interferon achieved even a minor response. Here, all the patients are alive, achieved complete cytogenetic and major molecular responses with a prolonged follow up, confirming thus the efficacy of imatinib mesylate in patients with rare BCR-ABL transcripts. Of note, in cases #2 and #3, the major molecular response was obtained after increasing the dosage of imatinib (400 to 600 mg/day), suggesting that those patients may require higher doses of imatinib to achieve proper molecular response. The aggressive clinical course of these leukemias could be shrouded by appropriate targeted therapy. A longer follow-up and the analysis of a large cohort of patients with e8a2 BCR-ABL fusions are necessary to analyse the clinical outcome of these patients. The study of these unusual transcripts is essential to gain more insights of their molecular pathological function and a more comprehensive survey of the different functions of the BCR-ABL chimeric protein.