NUS research breakthrough: CircASXL1-1 regulates BAP1 deubiquitinase activity in leukemia

August 13, 2020

Every year, 1.1 million new cases of blood cancers are diagnosed worldwide. Presently, chemotherapy remains the most common and effective course of treatment. However, the emergence of more aggressive forms of leukemia in adults prompts a need for early detection and new therapeutic approaches to achieve better clinical outcomes.

In a novel step forward, 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 leukemia development and provided greater understanding of their roles in haematological malignancies.

Mutations in additional sex combs-like 1 (ASXL1) gene, an epigenetics remodeler, have been found in acute myeloid leukemia (AML), chronic myelomonocytic leukemia (CMML) and myelodysplastic syndrome (MDS), and are associated with poor overall survival. Recently, the ASXL1 gene locus was shown to undergo alternative splicing to produce circRNAs. While previous studies on circRNAs have primarily been focused on understanding the origins of these non-coding RNAs, the CSI Singapore research group led by Assistant Professor Sudhakar Jha investigated the role of circRNAs in modulating the epigenetics landscape and the effects on differentiation in hematopoietic development and leukemogenesis.

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

New mechanism responsible for leukemia development

CircRNAs have been shown to have higher stability, are abundant, and highly conserved compared to linear RNAs. In addition, they can be detected in extracellular vesicles, exosomes and blood plasma thereby highlighting their potential as non-invasive biomarkers. Through RNA sequencing, the research team uncovered circRNA isoforms from the ASXL1 gene locus.

The team's analysis made inroads into understanding the role of circASXL1-1 in leukemia. Their data show that depletion of circASXL1-1 led to decreased H2AK119 ubiquitination (H2AK119ub) and this was through BRCA-1 associated protein 1 (BAP1) activity, a deubiquitinating enzyme and an important epigenetic regulator in leukemia. Furthermore, Asst Prof Jha and Dr Shweta Pradip Jadhav, a Research Fellow in his team, found that circASXL1-1 binds to BAP1 to regulate its catalytic activity.

"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," explained Asst Prof Jha.

Tapping on the newly established understanding, the research team aims to identify genes involved in myeloid differentiation program of haematopoietic stem cells (HSCs). These genes can in turn be targeted to restore the normal course of differentiation in leukemia or to help induce apoptosis of immature and abnormally differentiated cells. The epigenetic signature identified could thus pave the way for future therapeutic developments of "epi-drugs".

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


National University of Singapore

Related Leukemia Articles from Brightsurf:

New therapeutic approach against leukemia
Using an RNA molecule complex, researchers can prevent retention of cancer stem cell in their tumor supporting niche

Nanoparticle for overcoming leukemia treatment resistance
One of the largest problems with cancer treatment is the development of resistance to anticancer therapies.

Key gene in leukemia discovered
Acute myeloid leukemia (AML) is one of the most common forms of blood cancer among adults and is associated with a low survival rate, and leads to the inhibition of normal blood formation.

Vitamin B6, leukemia's deadly addiction
Researchers from CSHL and Memorial Sloan Kettering Cancer Center have discovered how Acute Myeloid Leukemia is addicted to vitamin B6.

Artificial intelligence tracks down leukemia
Artificial intelligence can detect one of the most common forms of blood cancer - acute myeloid leukemia -- with high reliability.

Milestone reached in new leukemia drug
Using a chemical compound called YKL-05-099, a team of cancer researchers from CSHL and the Dana Farber Institute was able to target the Salt-Inducible Kinase 3 (SIK3) pathway and extend survival in mice with MLL leukemia.

The drug combination effective against bovine leukemia
Scientists have succeeded in reducing levels of the bovine leukemia virus (BLV) in cows with severe infections by combining an immune checkpoint inhibitor and an enzyme inhibitor.

Towards a safer treatment for leukemia
An international team of researchers at VIB-KU Leuven, Belgium, the UK Dementia Institute and the Children's Cancer Institute, Australia, have found a safer treatment for a specific type of leukemia.

Research paves way for new source for leukemia drug
Chemistry researchers have patented a method for making anti-leukemia compounds that until now have only been available via an Asian tree that produces them.

An atlas of an aggressive leukemia
A team of researchers led by Bradley Bernstein at the Ludwig Center at Harvard has used single-cell technologies and machine learning to create a detailed 'atlas of cell states' for acute myeloid leukemia (AML) that could help improve treatment of the aggressive cancer.

Read More: Leukemia News and Leukemia Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.