The whole is greater than the sum of its parts: Long-read sequencing for solving clinical problems in haematology

Bravo‐Perez, C., Cifuentes‐Riquelme, R., Padilla, J., de la Morena‐Barrio, M. E., Ortuño, F. J., Garrido‐Rodríguez, P., Amigo, ML., Heras, I., Vicente, V., Lozano, ML., Teruel-Montoya, R., de la Morena-Barrio, B. & Corral, J. (2024). The whole is greater than the sum of its parts: Long‐read sequencing for solving clinical problems in haematology. Journal of Cellular and Molecular Medicine, 28(3), e17961.

DOi: 10.1111/jcmm.17961

Structural variations (SVs) are common in haematological neoplasms. Although most SVs have canonical breakpoints, virtually all have atypical rearrangements that can be of difficult diagnosis. High-throughput sequencing (HTS) has improved the study of atypical SVs, complementing cytogenetics. However, the short reads (<150 bp) generated by HTS might lead to inaccurate mapping. This may not suppose a mere technical pitfall, but a problem to be faced, to guarantee the monitoring and guided-treatment of patients bearing atypical SVs when standard procedures are ‘blind’ to them.

Inversion of chromosome 16, inv(16)(p13q22)/t(16;16)(p13;q22), found in 5%–7% of de novo acute myeloid leukaemia (AML), joins CBFB (16q22) and MYH11 (16p13) genes to form a chimeric oncoprotein that sequesters RUNX1. Up to 95% of cases with AML-inv(16) carry three recurrent breakpoints involving CBFB exon5, and MYH11 exon33, exon29 or exon28, resulting in type A, D or E transcripts, respectively.3 To the best of our knowledge, at least 10 additional CBFB::MYH11 transcripts with non-canonical breakpoints have been reported (Table 1). However, direct characterization of inv(16) at the genomic level has rarely been performed. In this context, third-generation HTS based on long reads, such as nanopore sequencing, could be excellent tools for the identification and comprehensive analysis of atypical SVs.