Every year, 1.1 million new cases of blood cancers are diagnosed globally. Currently, chemotherapy remains the most common and efficient plan of treatment. On the other hand, the development of aggressive types of leukemia in adults stimulates a need for early detection and new therapeutic approaches to achieve better clinical outcomes.

In a novel step ahead, researchers from the Cancer Science Institute of Singapore (CSI Singapore) at the National University of Singapore (NUS) have identified covalently closed circular RNAs (circRNAs) from key genes involved in embryonic growth and provided greater understanding of their functions in haematological malignancies.

This work has provided insights into a new mechanism for the regulation of H2AK119ub levels in hematopoietic progenitors via interaction of circASXL1-1 and BAP1,-Sudhakar Jha, Assistant Professor, Cancer Science Institute of Singapore, National University of Singapore

Mutations in additional sex combs-like 1 (ASXL1) receptor, an epigenetics remodeler, are found in acute myeloid leukemia (AML), chronic myelomonocytic leukemia (CMML) and myelodysplastic syndrome (MDS), and are associated with poor overall survival. Lately, the ASXL1 gene locus was shown to undergo alternative splicing to produce circRNAs.

While previous studies on circRNAs have mostly been concentrated on understanding the roots of the non-coding RNAs, the CSI Singapore research team headed by Assistant Professor Sudhakar Jha investigated the function of circRNAs in modulating the epigenetics landscape as well as the effects on differentiation in hematopoietic development and leukemogenesis.

The findings of this study were published in the prestigious scientific journal Haematologica in July 2020.

New mechanism accountable for leukemia development CircRNAs have been shown to have higher equilibrium, are plentiful, and highly conserved compared to linear RNAs.

In addition, they can be detected in extracellular vesicles, exosomes and blood plasma thus highlighting their possible as non invasive biomarkers. During RNA sequencing, the research team discovered circRNA isoforms in the ASXL1 gene locus.

The teams analysis made inroads into understanding the use of circASXL1-1 in leukemia. Their statistics show that depletion of circASXL1-1 led to decreased H2AK119 ubiquitination (H2AK119ub) and this had been through BRCA-1 related protein (BAP1) action, a deubiquitinating enzyme and a significant epigenetic regulator at leukemia. Tapping on the newly established comprehension, the research team aims to identify genes involved in myeloid differentiation program of haematopoietic stem cells (HSCs).

These enzymes can in turn be targeted to restore the normal path of differentiation in leukemia or to assist induce apoptosis of abnormally differentiated cells. The epigenetic signature recognized may thus pave the way for future therapeutic improvements ofepi-drugs.

Moving forward, the research team intends to create data supporting the use of circASXL1-1 in antisense therapy for malignant and non-malignant blood disorders using the recently obtained knowledge. More to the point, findings from this study will lay the foundation for the development of new RNA-based therapeutics for leukemia.

Source:

Journal reference:

Jadhav, S. P., circASXL1-1 regulates BAP1 deubiquitinase activity in leukemia. Haematologica.doi.org/10.3324/haematol.2019.225961.

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