Circular RNAs (circRNAs) are a group of long non-coding RNAs that have been discovered around three decades ago, but for many years their biological role remained unclear. Studies of the last years have expanded the knowledge of circ RNAs' functions in cells revealing their possible role as micro-RNA sponges, regulators of transcription and splicing, participants of ribosomal RNA processing, adaptors of protein-protein interactions and potentially translatable transcripts. Several investigations unveiled circRNAs' key role in cancer development being differentially expressed in many tumor tissues and cell lines and having both oncosupressor and oncogenic effects. Although some functional circRNAs have been observed in some solid tumors, implication of these molecules in hematological malignancies has been assessed by few studies dedicated to B-cell acute lymphoblastic leukemia and acute myeloblastic leukemia. Up to date nothing is known about the role of circRNAs in the mechanisms underlying T-cell acute lymphoblastic leukemia (T-ALL) .The current project is focused on identification and characterization of circRNAs involved in T-ALL onset, development and progression.
Pioneer RNA-seq based studies performed in hyperploid B-cell acute lymphoblast leukemia (B-ALL) blood samples in comparison with healthy primary blood cells demonstrated the existence of relatively big pool of circular transcripts in these cells [1, 2]. Unfortunately, these studies did not estimate quantitative differences between healthy and malignant tissue samples and did not shed light on circRNAs involved in deregulated hematopoesis during leukemia. Consequent re-estimation of published data allowed speculating that circRNAs from the genes responsible for B-ALL development are more present in leukemic cells comparing with normal primary lymphocytes [3]. Single evidences demonstrated the presence of small group of circular transcripts shared between several blood cell-types [1]. Though these data may help to have an idea about lineage-specific role of circRNAs, they are definitely not enough to recreate the full image of circRNAs involvement in normal and pathologic hematopoesis.
Actually, up to date the knowledge about circRNAs involvement in T-ALL is missed. The only evidence of circRNAs' implication in T-cell context was related to immunosenescence [4]. On the other hand, several studies indicate that long non-coding RNAs could sustain survival and proliferation in T-ALL cells by regulating the transcription of key oncogenes in T-ALL such as Notch1 [5, 6].
Investigations, performed on acute monocytic leukemia and chronic myelocytic leukemia cell lines, demonstrated that aberrant circRNAs can be generated from cancer-associated chromosomal translocations, and their presence does not only promote proliferative activity of these cells, but also leads to therapy resistance [7]. Information about circular transcripts of host genes involved in T-ALL development is restricted to RUNX-1 studied in other cell context [8].
Lack of any information regarding the role of circRNA in T-ALL development together with the known ability of long non-coding RNAs to modulate expression of oncogenes makes the search of possible circRNA maintaining tumor cells¿ survival and proliferation highly relevant. Unfortunately absence of correlation between circRNAs and molecular pathways responsible for cancer development makes it necessary to estimate differential expression of circRNAs in tumor and healthy tissues in order to narrow down the search area of candidate circular transcripts.
Our working hypothesis that circRNAs play a key role in the onset and/or progression of T-ALL could help to understand better T-ALL biology and causes and to allow the identification of novel therapeutic targets useful for the treatment of this disease.
References:
1. Memczak, S., et al., Circular RNAs are a large class of animal RNAs with regulatory potency. Nature, 2013. 495(7441): p. 333-8.
2. Salzman, J., et al., Circular RNAs are the predominant transcript isoform from hundreds of human genes in diverse cell types. PLoS One, 2012. 7(2): p. e30733.
3. Bonizzato, A., et al., CircRNAs in hematopoiesis and hematological malignancies. Blood Cancer J, 2016. 6(10): p. e483.
4. Wang, Y.H., et al., Comprehensive circular RNA profiling reveals that circular RNA100783 is involved in chronic CD28-associated CD8(+)T cell ageing. Immun Ageing, 2015. 12: p. 17.
5. Durinck, K., et al., The Notch driven long non-coding RNA repertoire in T-cell acute lymphoblastic leukemia. Haematologica, 2014. 99(12): p. 1808-16.
6. Wang, Y., et al., LncRNA NALT interaction with NOTCH1 promoted cell proliferation in pediatric T cell acute lymphoblastic leukemia. Sci Rep, 2015. 5: p. 13749.
7. Guarnerio, J., et al., Oncogenic Role of Fusion-circRNAs Derived from Cancer-Associated Chromosomal Translocations. Cell, 2016. 166(4): p. 1055-1056.
8. Xu, A.N., et al., Identification of a novel circularized transcript of the AML1 gene. BMB Rep, 2013. 46(3): p. 163-8.