Somatic mutations in the additional sex comb-like 1 (ASXL1) gene have been identified in multiple hematologic malignancies, including acute myeloid leukemia (AML), and are associated with poor prognoses1. ASXL1 encodes a nuclear protein that regulates epigenetic remodeling and transcription through interactions with polycomb complex proteins and transcriptional activators and repressors. Several ASXL1 mutations have been associated with loss of protein expression that leads to myeloid transformation2. In contrast, gain-of-function mutations in ASXL1 result in expression of a truncated ASXL1 protein that can bind to BRCA-1 associated protein 1 (BAP1) and cause leukemogenesis3,4. Targeted reduction of BAP1 activity is sufficient to prevent this malignancy process5.
A recent study has shown that the ASXL1 gene locus undergoes alternative splicing to produce circular RNAs (circRNAs) in addition to linear protein-coding mRNAs6. CircRNAs are non-coding RNAs that normally function as regulators of gene expression and translation by acting as sponges for microRNAs or forming complexes with RNA binding proteins. Here they identified two isoforms of circular ASXL1 (circASXL1), and they showed that circASXL1-1 can bind to BAP-1 and regulate BAP1-mediated deubiquitinase activity, which targets H2AK119 ubiquitination and regulates myeloid differentiation of hematopoietic stem cells. These findings suggest that circRNAs may be developed for use as novel therapeutics for the treatment of hematologic malignancies like AML.
- Pratcorona M, Abbas S, Sanders MA, et al. Acquired mutations in ASXL1 in acute myeloid leukemia: prevalence and prognostic value. Haematologica. 2012;97(3):388-392.
- Abdel-Wahab O, Adli M, LaFave LM, et al. ASXL1 mutations promote myeloid transformation through loss of PRC2-mediated gene repression. Cancer Cell. 2012;22(2):180-193.
- Balasubramani A, Larjo A, Bassein JA, et al. Cancer-associated ASXL1 mutations may act as gain-of-function mutations of the ASXL1-BAP1 complex. Nat Commun. 2015;6:7307.
- Asada S, Goyama S, Inoue D, et al. Mutant ASXL1 cooperates with BAP1 to promote myeloid leukaemogenesis. Nat Commun. 2018;9(1):2733
- Guo Y, Yang H, Chen S, et al. Reduced BAP1 activity prevents ASXL1 truncation-driven myeloid malignancy in vivo. Leukemia. 2018;32(8):1834-1837.
- Jadhav SP, Kumari N, Ng L, et al. circASXL1-1 regulates BAP1 deubiquitinase activity in leukemia. Haematologica, 2020; 105 (7): e343 DOI: 10.3324/haematol.2019.225961.