KMT2E-ASNS: a novel relapse-specific fusion gene in early T-cell precursor acute lymphoblastic leukemia

2][3] This heterogeneous subgroup shows a distinctive immature immunophenotype characterized by the differential expression of cell surface markers during T-cell development. 2,4][9] ETP-ALLs are associated with multiple rearrangements affecting gene-coding regions, quite possibly with a bearing on the formation of novel chimeric fusion genes, 2,4,10,11 for which the clinical significance remains as yet largely unknown.In order to better understand the factors leading to childhood ETP-ALL relapse, the whole transcriptome of 2 ETP-ALL patients was investigated with a view toward identifying relapse-specific rearrangements.The 2 patients (TC0002 and TC0022) were diagnosed with ALL at 12 and 16 years of age, respectively, and immunophenotyping revealed antigenic determinants corresponding to ETP-ALL subtype.Both of them were classified as high risk and treated with an L-asparaginase- intensive chemotherapy regimen, according to Dana-Farber Cancer Institute Childhood ALL Consortium protocol for high-risk patients.In both cases, the patients relapsed, after 5 and 2 years respectively, after having obtained an initial remission.The whole transcriptome analysis revealed a novel recurrent fusion transcript linking the 59 untranslated region (UTR) of KMT2E to the entire coding sequence of ASNS, indicating a promoter swap (Figure 1A-B).Quantitative reverse transcription polymerase chain reaction (RT-qPCR) was performed at diagnosis, in conjunction with bone marrow samples taken at different time points after induction treatment of TC0002, and these indicated that the fusion was relapse specific (Figure 1C-D).This novel recurrent fusion may have been previously overlooked in other studies as a consequence of the rarity of transcriptome analysis having being performed on relapsed ETP-ALL, as this may indeed be the sole recorded study.KMT2E and ASNS are located ; 7.1 Mb apart on chromosome 7, in opposite orientations (supplemental Figure 1A, available on the Blood Web site), implying that the observed KMT2E-ASNS transcripts may be the result of a cryptic inversion [inv(7)(q22.3q21.3)].In spite of the absence of a reciprocal ASNS-KMT2E transcript, we observed a transcript linking the 59 portion of the MGC72080 pseudogene (located ;40 kb upstream of ASNS) to exon 2 of KMT2E in the relapse material of both of these patients, which supports the chromosomal inversion hypothesis (supplemental Figure 1B).To assess the impact of the promoter swap on ASNS expression, we measured the expression levels of KMT2E, ASNS, and KMT2E-ASNS

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