Leukemia breakthrough: CircASXL1-1 regulates BAP1 deubiquitinase
activity in leukemia

Date:
August 13, 2020
Source:
National University of Singapore
Summary:
Researchers have identified covalently closed circular RNAs
(circRNAs) from key genes involved in leukemia development and
provided greater understanding of their roles in haematological
malignancies.



FULL STORY ========================================================================== 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 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.


========================================================================== Story Source: Materials provided by
National_University_of_Singapore. Note: Content may be edited for style
and length.


========================================================================== Journal Reference:
1. Shweta Pradip Jadhav, Nishi Kumari, Larry Ng, Pei Fang Tan,
Nicole Shu
Ling Yeo-Teh, Yufen Goh, Wee Nih Fam, Jia Qi Tng, Johann Shane Tian,
Bryan T. H. Koh, Chan Ming Chun, Wilson Wang, Wee Joo Chng, Melissa
Jane Fullwood, Ernesto Guccione, Neerja Karnani, Daniel G. Tenen,
Sudhakar Jha. circASXL1-1 regulates BAP1 deubiquitinase activity
in leukemia.

Haematologica, 2020; 105 (7): e343 DOI: 10.3324/haematol.2019.225961 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2020/08/200813103123.htm

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