CircRNAs Are Here to Stay: A Perspective on the MLL Recombinome.

Anna Dal Molin,Lueder H Meyer,Caterina Tretti,Paola Guglielmelli,Silvia Bresolin,Elena Boldrin,Geertruij Te Kronnie,Enrico Gaffo,Stefania Bortoluzzi,Alessandro M Vannucchi

doi:10.3389/fgene.2019.00088

Anna Dal Molin, Lueder H Meyer + Show 8 more

Open Access

https://doi.org/10.3389/fgene.2019.00088

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Abstract

Chromosomal translocations harbored by cancer genomes are important oncogenic drivers. In MLL rearranged acute leukemia (MLLre) MLL/KMT2A fuses with over 90 partner genes. Mechanistic studies provided clues of MLL fusion protein leukemogenic potential, but models failed to fully recapitulate the disease. Recently, expression of oncogenic fusion circular RNAs (f-circ) by MLL-AF9 fusion was proven. This discovery, together with emerging data on the importance and diversity of circRNAs formed the incentive to study the circRNAs of the MLL recombinome. Through interactions with other RNAs, such as microRNAs, and with proteins, circRNAs regulate cellular processes also related to cancer development. CircRNAs can translate into functional peptides too. MLL and most of the 90 MLL translocation partners do express circRNAs and exploration of our RNA-seq dataset of sorted blood cell populations provided new data on alternative circular isoform generation and expression variability of circRNAs of the MLL recombinome. Further, we provided evidence that rearrangements of MLL and three of the main translocation partner genes can impact circRNA expression, supported also by preliminary observations in leukemic cells. The emerging picture underpins the view that circRNAs are worthwhile to be considered when studying MLLre leukemias and provides a new perspective on the impact of chromosomal translocations in cancer cells at large.

Highlights

Anna Dal Molin1, Silvia Bresolin2, Enrico Gaffo2, Caterina Tretti2, Elena Boldrin3, Lueder H
As long as non-coding RNAs, circRNAs have some coding potential, and can be translated into functional peptides according to recent reports (Legnini et al, 2017; Pamudurti et al, 2017; Yang et al, 2017). Taken together these discoveries of circRNA pervasiveness and functions prompted us to study the circRNAs expressed by genes of the MLL recombinome (MLL-rec) in normal blood cells. In this perspective we examined how rearrangements can result in alteration of sequences and expression level of circRNAs normally generated by MLL and translocation partner genes (TPGs), and provided data of MLL rearranged acute leukemia (MLLre) leukemia in support
Data emerging from recent literature and from the present study collectively show that KMT2A and TPGs express many circRNAs, FIGURE 2 | CircRNAs expressed by KMT2A and 3 TPGs among the most recurrent in acute leukemias

Summary

Introduction

Anna Dal Molin1, Silvia Bresolin2, Enrico Gaffo2, Caterina Tretti2, Elena Boldrin3, Lueder H. We provided evidence that rearrangements of MLL and three of the main translocation partner genes can impact circRNA expression, supported by preliminary observations in leukemic cells.

Results

Conclusion