Health
Covalently closed circular RNA regulates BAP1 deubiquitinase activity in leukemia
Bone marrow aspirate showing acute myelogenous leukemia. Some blasts have auer rods. Credit: Wikipedia
Each year, 1.1 million new blood cancer cases are diagnosed worldwide. Chemotherapy remains the most common and effective treatment strategy today. However, the emergence of more aggressive forms of leukemia in adults has prompted the need for early detection and new therapeutic approaches to achieve better clinical outcomes.
As a new step forward, researchers at the Singapore Cancer Science Institute (CSI Singapore) at the National University of Singapore (NUS) leukemia It provided a greater understanding of development and their role in hematological malignancies.
Additional sex-comb-like 1 (ASXL1) gene, epigenetics remodeler mutations found Acute myeloid leukemia (AML), chronic myelomonocytic leukemia (CMML) and myelodysplastic syndrome (MDS), and reduced overall survival. Recently, the ASXL1 locus has been shown to undergo alternative splicing to generate circRNAs. While previous work on circRNAs has largely focused on understanding the origins of these non-coding RNAs, the CSI Singapore research group headed by Associate Professor Sudhakar Jha has focused on the regulation of the epigenetic context. We investigated the role of circRNAs and their effects on differentiation in hematopoietic development and differentiation of leukemia.
Research findings published in prestigious scientific journals Hematology July 2020.
A new mechanism involved in the development of leukemia
CircRNA is more stable, abundant, and highly conserved than linear RNA. In addition, it can be detected in extracellular vesicles, exosomes, and plasma, highlighting its potential as a non-invasive biomarker. By RNA sequencing, the team discovered a circRNA isoform at the ASXL1 locus.
The team’s analysis permeated the understanding of the role of circASXL1-1 in leukemia. Their data indicate that depletion of circASXL1-1 led to reduced H2AK119 ubiquitination (H2AK119ub), via BRCA-1-related protein 1 (BAP1) activity, deubiquitinating enzymes, and key epigenetic regulators in leukemia It shows that. In addition, Professor Asst Jha and Dr. Shweta Pradip Jadhav, a researcher on his team, discovered that circASXL1-1 binds to BAP1 and regulates its catalytic activity.
“This study provided insights into a new mechanism for the regulation of H2AK119ub levels in hematopoietic progenitor cells through the interaction of circASXL1-1 and BAP1,” Asst professor Jha explained.
Using the newly established understanding, the research team aims to identify genes involved in the hematopoietic stem cell (HSC) myeloid differentiation program. These genes may then be targeted to restore the process of normal differentiation in leukemia, or to help induce apoptosis of immature, aberrantly differentiated cells. Therefore, the identified epigenetic signatures may pave the way for future therapeutic development of “epidrugs”.
In the future, the research team will use the newly acquired knowledge to generate data to support the use of circASXL1-1 in antisense therapy for malignant and non-malignant hematological disorders. More importantly, the results of this study will lay the foundation for the development of new RNA-based therapies for leukemia.
Shweta Pradip Jadhav et al. circASXL1-1 regulates BAP1 deubiquitinase activity in leukemia, Hematology (2019). DOI: 10.3324 / haematol.2019.225961
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National University of Singapore
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