CircRNA: a rising star in leukemia

Introduction

Leukemia is a type of blood cancer derived from hematopoietic stem and progenitor cells (Khodakarami et al., 2022). These cells have lost the ability for self-renewal, differentiation, and apoptosis (Milan et al., 2019). Globally, 437,033 people were diagnosed with leukemia in 2018, making it one of the most common cancers (Bispo, Pinheiro & Kobetz, 2020). This disease caused 309,006 cancer deaths and ranked as the 11th leading cause of cancer death for both men and women according to GLOBOCAN 2018 data (Bispo, Pinheiro & Kobetz, 2020). Leukemia can be classified into four main categories, including acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), chronic myeloid leukemia (CML), and chronic lymphocytic leukemia (CLL) (Bhat et al., 2020; Deng, Chao & Zhu, 2023; Perez de Acha, Rossi & Gorospe, 2020). AML is the most common form of acute leukemia found in adults (Greiner, Gotz & Wais, 2022; Kang et al., 2022; Pinto-Merino et al., 2022). It is an aggressive and heterogeneous disease characterized by rapid proliferation and arrested differentiation of medulloblastoma in the peripheral blood, bone marrow, and other tissues (Shapoorian, Zalpoor & Ganjalikhani-Hakemi, 2021; Xiang et al., 2022). ALL is a highly-aggressive hematological disease (Li et al., 2022; Xin et al., 2022). ALL patients are characterized by an abnormal proliferation and aggregation of lymphocytes in the bone marrow. Lymphocytes are transferred to other tissues and organs, infiltrating systemic organs and tissues, and seriously affecting the hematopoietic function of the bone marrow (Ruchel et al., 2022; Tan, Bertulfo & Sanda, 2017). CML is a myeloproliferative neoplasm characterized by the proliferation of clonal hematopoietic stem cells (Minciacchi, Kumar & Krause, 2021; Sampaio et al., 2021). It is a relatively rare disorder with an annual incidence of 0.7–1 cases per 100,000 individuals with a lower incidence in females than in males (Andretta et al., 2021). CLL is the most common lymphoproliferative disease. The disease causes CD5+ B cells to proliferate and accumulate in the blood, spleen, lymph nodes, and bone marrow (Hallek, 2019; Iovino & Shadman, 2020; Scheffold & Stilgenbauer, 2020).

Circular RNAs (circRNAs) are an abundant class of endogenous noncoding RNAs (ncRNAs) that are characterized by covalently closed loop structures with no exposed 3′  and 5′  ends (Chen & Shan, 2021; Kristensen et al., 2019; Zhou et al., 2020). This structure was first described in viroids and were later found to be widely expressed in eukaryotic organisms (Memczak et al., 2013; Wang et al., 2014; Wilusz & Sharp, 2013). CircRNAs are divided into four types based on where they originate, namely exonic circRNAs, intronic circRNAs, exon-intron circRNAs, and intergenic circRNAs (Chen et al., 2021; Wang et al., 2020; Wang & Ji, 2016). CircRNAs have specialized structures and properties which allow them to be involved in various biogenesis processes (Chen & Shan, 2021; Zhang, Hu & Yu, 2020a). The literature reports that circRNAs participate in physiological and pathological processes in four unique ways (Cui et al., 2020; Jamal et al., 2019; Wu, Li & Jin, 2019). Firstly, it acts as a miRNA sponge (Fig. 1A). Increasing evidence suggests that circRNAs contain miRNA binding sites, and circRNAs can block miRNA binding to the 3′-UTR region of target mRNAs, thereby regulating the expression of mRNAs (Jin et al., 2020; Li et al., 2020b; Rajappa et al., 2020; Zhang et al., 2020b). Secondly, it regulates gene transcription. Most of the circRNAs exist in the cytoplasm, but a small fraction of circRNAs also exist in the nucleus, such as ciRNAs and ElciRNAs, suggesting that circRNAs may be involved in the transcriptional regulation of parental genes (Fig. 1B) (Kumari et al., 2022; Li et al., 2020a; Wang et al., 2020; Zhou et al., 2022b). CiRNAs and ElciRNAs regulate gene transcription differently. CiRNAs act mainly through their accumulation in the transcriptional region of the parental gene, enhancing the polymerase II (Pol II) extension activity to regulate transcription (Li et al., 2020a). However, EIciRNAs promote transcription mainly by interacting with the U1 small ribonucleic acid protein (snRNP) in the gene promoter region and binding to polymerase II (Pol II) (Sun et al., 2020). Thirdly, circRNA interaction with RBPs. CircRNAs can act on different proteins to form circular RNA-protein complexes (circRNPs) to regulate protein action, the subcellular localization of proteins or the expression of target genes (Fig. 1C) (Qian et al., 2021; Singh et al., 2021; Sun et al., 2020). Some circRNAs can act as a decoy to regulate gene expression by binding or dissociating proteins and some circRNAs are able to be used as protein scaffolds to mediate protein-protein interactions. Fourthly, accumulating evidence has shown that circRNAs can be translated into peptides or proteins, even though the noncoding properties of circRNAs are traditionally due to the absence of 5′  and 3′  ends (Fig. 1D) (Pamudurti et al., 2017; Schneider & Bindereif, 2017; Yang et al., 2017).

The current research on circRNAs in leukemia is not comprehensive. Here, we briefly review the impact of the expression and function of circRNAs on different human leukemias, focusing on the role of circRNAs in leukemia immunomodulation and chemoresistance, as well as the potential of circRNAs in leukemia diagnosis and prognosis. This review help researchers to quickly understand the recent research progress of circRNAs in human leukemia and provide valuable information for future research directions.

Survey Methodology

To ensure an inclusive and unbiased analysis of the literature and to accomplish the review objectives, we searched the following literature databases: PubMed, Google Scholar and Web of Science. The search terms included: circRNA, leukemia, chemoresistance, immune modulation, and biomarker. It is worth noting that the keywords used and their variants and related words can be sorted, combined, and then searched.

1. The terms searched for circRNA were: circRNA, circular RNA, noncoding RNA, circular intronic RNA, exon-intron circRNA, epigenetic, epigenetic regulation.

2. The terms searched for leukemia were: leukemia, acute myeloid leukemia, acute myeloid leukemia, chronic myeloid leukemia, chronic lymphocytic leukemia, AML, ALL, CML, CLL.

3. The terms searched for circRNA and leukemia were: chemoresistance, immune modulation, biomarker.

This article is based on published literature. The aspects of the inclusion criteria are the retrieval keywords, information not covered by previous literature, and most importantly, the use of a clear and credible source.

Role of circRNAs in chemoresistance in leukemia

As with many other cancers, drug resistance in leukemia patients is a difficult issue to address. Commonly used drugs for the treatment of leukemia, such as rituximab, chlorambucil, bendamustine, etc., have obvious curative effects in the early stages of administration. Over time, however, the efficacy of these drugs declines significantly, and leukemia patients may develop resistance to these drugs. Growing evidence has suggested that circRNAs significantly impact the chemoresistance of leukemia patients (Fig. 2). Cao et al. (2020) demonstrated that Circ_0009910 was up-regulated in imatinib-resistant CML patient cells and it promoted imatinib-resistance by targeting miR-34a-5p to regulate ULK1 and induce autophagy. Similarly, circBA9.3 was shown to be upregulated in CML patients. CircBA9.3 could promote the resistance of CML cells to treatment with tyrosine kinase inhibitors (TKIs), suggesting that circBA9.3 might be a target for drug resistance in CML patients (Pan et al., 2018). Ding et al. (2021) found that circNPM1 could promote the resistance of AML cells to adriamycin via the miR-345-5p/FZD5 axis, indicating that circNPM1 was a potential marker in AML drug resistance therapy. circPAN3 was found to be abnormally highly expressed in doxorubicin-resistant AML cells, indicating that circPAN3 may promote AML resistance to doxorubicin by regulating cellular autophagy and affecting apoptosis-related proteins expression through the AMPK/mTOR signaling pathway (Shang et al., 2019). In addition, hsa_circ_0058493 was highly expressed in peripheral blood mononuclear cells (PBMCs) of CML patients, and its high expression was closely related to the poor clinical efficacy of imatinib. Therefore, hsa_circ_0058493 may be a new strategy for the treatment of CML (Zhong et al., 2021). Ping et al. (2019a) found that circ_100053 was significantly up-regulated in the serum of imatinib-resistant CML patients, and the expression of circ_100053 was correlated with its clinical stage. circ_100053 may be a potential biomarker of imatinib resistance in CML (Ping et al., 2019a). The above studies suggest that circRNAs do play an important role in chemoresistance in leukemia patients. It may be possible to use existing tools to develop relevant reagents for circRNAs that can treat chemoresistance in leukemia patients. In this way, the suffering caused by the disease may be alleviated in patients.

Conclusions and Perspectives

At present, chemotherapy remains one of the most effective methods of treatment for leukemia. With the rapid development of technology, circRNAs have opened up a new research field as a novel type of non-coding RNA. Increasing evidence suggests that circRNAs can broadly regulate human physiological and pathological processes, especially in leukemia. In this review, we provided an overview of the latest research advances in circRNAs and highlighted the role they play in leukemia.

Increasing amounts of research have shown that circRNAs are aberrantly expressed in leukemia (Table 1). CircRNAs can serve as potential indicators or therapeutic targets for leukemia diagnosis and treatment. For example, circ_0009910 is upregulated in AML, and circ_0009910 can be used as a biomarker for its poor diagnosis and prognosis (Ping et al., 2019b). Meanwhile, circRNAs can act as oncogene or tumor suppressor genes to regulate the proliferation, apoptosis, cycle, differentiation, migration, invasion, autophagy, and other processes in leukemia, which play a crucial role in the occurrence and development of leukemia. In addition, circRNAs play a role in chemoresistance in leukemia. For example, circPAN3 regulates autophagy and affects the expression of apoptosis-related proteins through the AMPK/mTOR signaling pathway, resulting in AML resistance to doxorubicin (Shang et al., 2019). Furthermore, circRNAs are involved in the immune modulation of leukemia. For example, hsa_circ_0075001 can be involved in the toll-like receptor signaling pathway and participate in the immune modulation of AML (Hirsch et al., 2017). However, the research on circRNAs has been limited to in vitro experiments such as cells and tissues, and has not been applied to the clinical setting. Therefore, we need to increase our preclinical investment to explore effective methods of applying circRNAs as biomarkers for the diagnosis and prognosis in leukemia in vivo. First, more in vitro experiments should be conducted to screen for efficient and expected circRNAs. Second, a robust circRNA database should be established, especially those with tissue specificity. Third, novel tools and methods should be developed to improve the specificity of circRNA detection. In conclusion, circRNAs are a class of regulatory factors that can play an important role in leukemia, and they can regulate the occurrence and development of leukemia. Therefore, it is necessary to strengthen the research on circRNAs in the future so that the results can be transferred from in vitro research to in vivo research. These applications will better serve those affected by leukemia and will allow for the development of precision medicine in the near future.