Introduction
Multiple myeloma (MM) is a hematological malignancy characterized by abnormal proliferation of bone marrow plasma cells, which is prevalent in elderly population and has complex pathogenic factors. Despite significant progress in the treatment of MM, there are still patients experience high recurrences. Therefore, it is essential to search for new targets for diagnosis, treatment, and prognosis of MM. The N6-methyladenosine methylation (m6A) modification is one of the most abundant dynamic RNA modifications among the many other RNA modifications discovered today. In recent years, the increasing studies on the relationship between m6A modification and non-coding RNAs (ncRNAs) had suggested that they interact with each other and the potential in occurrence and progression of MM, which makes m6A and ncRNAs a promising treatment target in MM.
m6A modification and MM
Research progress on m6A modification
As a malignant tumor of the hematological system, there are still many gaps in the molecular mechanisms of its occurrence, development, and prognosis. Understanding the relevant mechanisms of the course of MM will provide new options for the treatment of its patients [ 1 ]. M6A modification is a common RNA modification in eukaryotes [ 2 ], and it has been found in microRNAs (miRNAs), long noncoding RNAs (lncRNAs), and circular RNAs (circRNAs) [ 3 ]. M6A modification may alter gene expression and function, thereby affecting disease progression. In recent years, many studies have elucidated the key role of m6A modification in various cancers, such as colorectal cancer [ 4 ], and gastric cancer [ 5 ]. Its roles in hematological diseases, such as leukemia [ 6 ], lymphoma [ 7 ], and MM [ 8 ] had also been explored. Specifically in MM, various stages of m6A modification is correlated with different stages of MM occurrence [ 9 ], progression [ 10 , 11 ], prognosis [ 9 ], and treatment [ 12 , 13 ]. However, the specific mechanism of regulation still needs further exploration.
The regulators of m6A can be divided into encoders, decoders, and readers, namely methyltransferases, m6A demethylases, and m6A methylated reading proteins [ 14 ]. Among them, m6A methyltransferase can cause m6A modification of mRNA bases, specifically methyltransferase like 3 (METTL3), methyltransferase like 14 (METTL14), and Wilms' tumor 1-associating protein (WTAP), which are core proteins of m6A methyltransferase. The m6A demethylases include Fat mass and obesity-associated protein (FTO) and Human Alk B homolog 5 (ALKBH5), where FTO has been shown to be closely related to acute myeloid leukemia [ 15 ]. In addition, m6A-methylated reading proteins can specifically bind to m6A-methylated regions, participate in downstream mRNA translation degradation and miRNA processing, and intervene in various disease processes. Known reading proteins such as YTH N6-Methyladenosine RNA Binding Protein C1-2 (YTHDC1-2) [ 16 ], YTH N6-Methyladenosine RNA Binding Protein C1-3 (YTHDF1-3) [ 17 ], eukaryotic initiation factor 3 (eIF3), and Heterogeneous Nuclear Ribonucleoprotein A2/B1 (HNRNPA2B1) [ 18 ] are involved in m6A modification and are closely related to cancer and immune system diseases.
Research progress on the relationship between m6A modification and MM
Research has shown that m6A modification and its regulatory factors are dysregulated in many cancers, and almost all known m6A regulatory proteins regulate tumor cells and disease progression by targeting specific genes. For example, METTL14 can promote the invasiveness of acute myeloid leukemia by regulating the m6A modification of Zinc Finger E-Box Binding Homeobox 1 (ZEB1) [ 19 ], while in hepatocellular carcinoma, inhibiting the m6A modification of circFUT8 can suppress disease progression [ 20 ]. These two studies have demonstrated the important role of m6A modification in disease progression, making us realize the bidirectional regulation of m6A modification can control disease progression. Therefore, targeted regulation of m6A modification via inhibitors or agonists is a promising strategy for disease treatment, especially for cancer treatment, which requires more in-depth research.
The role of m6A methylation-related enzymes in MM has been extensively studied, intervening in various aspects such as MM tumor growth [ 1 ], cell proliferation [ 21 , 22 ] and osteoclastogenesis [ 23 ]. METTL3 is significantly upregulated in MM and promotes tumor growth via the miR-182/CAMK2N1 signaling axis [ 1 ]. It also stabilizes YY1 mRNA and facilitates the maturation of miR-27a-3p, thereby influencing MM cell proliferation, apoptosis, and stemness [ 21 ]. Conversely, inhibiting METTL3-mediated m6A methylation has been shown to reduce MM cell proliferation [ 22 ]. These findings collectively suggest that METTL3 is a critical driver of MM progression. However, conflicting evidence exists regarding the role of METTL3 in MM. While most studies highlight its oncogenic role, some suggest that METTL3's effects may be context-dependent, with potential variations across different MM subtypes [ 22 , 24 ]. This complexity underscores the need for a nuanced understanding of METTL3's function in MM.Targeting METTL3 offers potential therapeutic benefits but also presents significant challenges. However, translating these findings into clinical practice is complicated by several factors. First, developing specific METTL3 inhibitors that do not affect other m6A methyltransferases is technically challenging. Second, ensuring efficient delivery of these inhibitors to MM cells while minimizing systemic toxicity remains a major hurdle. Third, METTL3's role in normal cellular processes raises concerns about potential off-target effects, which could lead to unintended adverse effects. Despite these challenges, targeting METTL3 presents notable opportunities. Future research should focus on developing specific inhibitors, optimizing delivery methods, and identifying predictive biomarkers to improve outcomes for MM patients.
Research has found that heat shock factor 1 (HSF1) is a m6A-modified functional target mediated by m6A demethylase FTO. FTO targets HSF1 in a YTHDF2-dependent manner, significantly promoting the proliferation, migration, and invasion of MM cells [ 25 ]. Simultaneously, high expression of FTO can also enhance MM's resistance to bortezomib [ 26 ], increasing the difficulty of clinical treatment. Therefore, reducing FTO expression could be a potential new therapeutic approach for MM.
ALKBH5 is a demethylase that affects RNA output and metabolism, playing an important role in the occurrence and development of tumors. It is highly expressed in primary MM cell lines isolated from patients and it can promote the proliferation, invasion, and migration ability of MM cells [ 27 ]. Concurrently, experiments have found that ALKBH5 can activate the NF-κB and MAPK signaling pathways to promote growth and survival of MM cells [ 28 ]. We speculate that ALKBH5 knock out can induce apoptosis, thus reduce proliferation and migration ability of MM cells. Therefore, a ALKBH5 prognostic marker is effective for the diagnosis of MM and ALKBH5 inhibitors may have therapeutic effects on MM.
As m6A-reading proteins, HNRNPA2B1 and YTHDF2 have been implicated in promoting the proliferation of multiple myeloma (MM) cells and are associated with disease severity and poor prognosis [ 29 – 31 ]. Similarly, other m6A-reading proteins such as HNRNPC and FTP have been identified as prognostic markers for adverse clinical outcomes [ 32 , 33 ]. These findings collectively suggest that m6A-reading proteins are strong predictors of unfavorable disease progression and could serve as potential therapeutic targets in MM.
However, it is crucial to critically evaluate the evidence and consider potential differences in the mechanisms by which these proteins contribute to MM progression. While HNRNPA2B1 and YTHDF2 are consistently associated with poor outcomes, their specific roles in MM biology may vary. For instance, HNRNPA2B1 may influence RNA metabolism through metabolism and inflammation compared to YTHDF2, which primarily affects mRNA translation and stability.
Studies have confirmed that protein arginine methyltransferase 1 (PRMT1) can methylate the key component Wilms' tumor 1-associating protein (WTAP) of the m6A methyltransferase complex. Knocking down PRMT1 reduces oxidative phosphorylation in MM cells and inhibits proliferation [ 8 ]. This underscores the importance of m6A modification in MM development and suggests that PRMT1 could be a potential therapeutic target. However, the development of small molecules or inhibitors that selectively target these proteins remains a technical challenge. So the clinical application of such inhibitors will require careful consideration of potential side effects and the development of specific delivery methods to minimize off-target impacts.
In summary, the m6A regulatory proteins, such as METTL3, FTO, ALKBH5, HNRNPA2B1, YTHDF2, and PRMT1 play important roles in the progression of multiple myeloma. METTL3, FTO, and YTHDF2 had been extensively study for their roles in apoptosis, proliferation, osteoclastogenesis, and drug resistance (Fig. 1 ). They are valuable diagnostic markers and promising treatment targets of MM. However targeting these m6A regulators presents both opportunities and challenges, with future research focusing on developing specific inhibitors, optimizing delivery methods, and identifying predictive biomarkers to improve outcomes for MM patients. Fig. 1 Key targets and functions of m6A modification in multiple myeloma. Methylase type (green boxes): methyltransferase, demethylase, methylated reading protein. Core Regulatory Proteins (orange boxes): METTL3, PRMT1, ALKBH5, FTO, HNRNPA2B1, YTHDC2, eIF3. Intervention mechanism and approach (blue boxes): apoptosis, miR-182, cell proliferation, Osteoclast migration, oxidative phosphorylation, N F-κB MAPK, proliferation and migration, RNA Metabolism, apoptosis, cell proliferation
ncRNA
Progress in ncRNA research
ncRNA refers to RNA that does not encode proteins, and currently, the most commonly studied include miRNA, lncRNA, and circRNA. ncRNA can play a role at both the transcriptional and post-transcriptional levels [ 34 ] and in epigenetic regulation of gene expression [ 35 ]. It involves various biological processes and has been shown to have impacts on various diseases, ranging from different stages of disease occurrence to development.
Relationship between circRNA and MM
circRNA has been extensively studied in cancer, such as lung cancer [ 36 ], gastric cancer [ 37 ], and prostate cancer [ 38 ]. It is also been explored in immunoproliferative cancers, such as osteosarcoma [ 39 ], acute lymphoma [ 40 ], acute lymphocytic leukemia [ 41 ], and multiple myeloma. The extensive research on circRNA in MM demonstrated that circRNA can intervene in the progression of MM through various pathways. One of the most common is by activating downstream target proteins of miRNA to intervene cell proliferation. Experiments have shown that the downregulation of Circ_0005615 can target miR-331-3p/IGF1R axis and thus block MM cells proliferation [ 42 ]. Therefore, inhibit Circ_0005615 expression can be a novel approach for MM treatment. circRNA can also affect apoptosis of MM cells, thereby influencing the progression of MM [ 43 ].
Studies have found that high expression of circXPO1 [ 44 ] and circ_0000190 [ 45 ] can promote the progression of MM. On the other hand, circ_0111738 can inhibit the oncogenic function of miR-1233-3p in MM patients [ 46 ], implying that circRNA regulation is bi-directional.
circRNA plays an significant role in the prognosis of multiple myeloma. High expression of circRFWD_2369aa [ 47 ] and circCCT3 [ 48 ] is correlated with poor prognosis. circ_0001821 can regulate the proliferation and apoptosis of MM cells and represents a poor prognosis of multiple myeloma [ 43 ].
In conclusion, the abnormal expression of circRNAs in MM may have significant implications for the treatment of MM. They can serve as prognostic markers for disease progression. circRNAs’ functions in cell proliferation suggesting that appropriate regulation of their expression is a possible therapeutic avenue for MM patients. Nearby, Lipid Nanoparticles (LNPs) have been successfully used to deliver circRNA-based therapeutics. LNPs in MM has also begun to be explored preliminarily. I believe that this could be a promising direction for applying circRNAs in the treatment of MM.
Relationship between lncRNA and MM
The relationship between lncRNA and MM involves various aspects of diagnosis, development, and treatment. Its significance in diagnosis has been extensively studied. Through retrospective analysis and PCR validation, it was found that the expression of lncRNA CATG00000112921.1 was reduced in newly diagnosed MM patients compared to healthy controls. The study inferred that lncRNA CATG00000112921.1 may serve as a diagnostic marker for MM [ 49 ]. However, this experiment has certain limitations, such as small sample size and only one type of lncRNAs was validated. Further research is required to verify the differences in lncRNA expression between newly diagnosed MM patients and normal individuals, with a larger sample size to enhance the credibility of the experimental results and provide more evidence for lncRNA as a diagnostic marker for MM.
Many experimental studies have described various roles of lncRNA on MM progression. lncRNA FEZF1-AS1 can accelerate the progression through IGF2BP1/BZW2 signaling [ 50 ], while lncRNA NBR 2 can inhibit MM growth by activating the AMPK/mTOR pathway [ 51 ]. From these data, we inferred that lncRNA have both cell-proliferative and regulatory effect on MM, providing new ideas for repressing disease progression.
As a disease that has yet to be cured, it is urgent to search for therapeutic targets for MM. Currently, there are many studies exploring the therapeutic effect of lncRNA. For example, lncRNA NORAD and lncRNA NEAT1 can affect apoptosis in MM cells [ 52 , 53 ]. High-expression LncRNA MALAT1 can promote MM tumorigenicity and angiogenesis [ 54 ], and high-expression LncRNA NEAT1 can promote MM cell immune escape [ 55 ]. LncRNA H19 can participate in osteoclast differentiation [ 56 ], and lncRNA MALAT1 silencing can inhibit MM cell proliferation and invasion [ 57 ]. These studies verified the important role of lncRNA in MM progression. However, delivering lncRNA-targeted drugs to MM cells remains a significant challenge. Currently, commonly used delivery systems include LNPs and viral vectors, which still have issues such as immunogenicity, delivery efficiency, and targeting accuracy. In the future, it will be necessary to develop more efficient and safer delivery systems to ensure that drugs can accurately reach the target cells and exert their therapeutic effects.
Relationship between miRNA and MM
There are significant differences in miRNA expression between healthy individuals and MM patients. Experiments have shown that upregulation of miR-26 expression inhibits MM cell proliferation and promotes apoptosis [ 58 ], similarly, miR-1179 also inhibits the progression by promoting apoptosis [ 59 ], suggesting that apoptosis may be an important pathway for miRNA intervention. On the other hand, some studies have found that upregulation of miR-182 promotes the metastasis of MM cells [ 60 ]. These indicate that miRNA plays both a regulatory and proliferative role in MM development. Therefore, development of miRNA-related targeted drugs to regulate miRNA expression levels may be a new avenue to accelerate apoptosis, reduce metastasis, and inhibit MM progression.
miRNA not only serve important roles in multiple myeloma (MM) growth but also resistance of existing MM treatment. Studies have shown that high expression of miR-182 enhances resistance to cabozantinib [ 60 ], high expression of miR-140-5p and miR-28-3p also resist bortezomib [ 61 ], and overexpression of miR-34a suppresses the activity and tumoricidal effect of CAR-T cells [ 62 ]. Therefore, regulating miRNA can not only control MM progression, but it also reduce patient resistance to existing therapies and enhance treatment efficacy, with the promise to prolong patient survival.
Finally, miRNA also plays a role in predicting MM prognosis. Studies have found that the expression of has-miR-223-3p [ 63 ], miR-16, and miR-21 [ 64 ] in the serum of MM patients changes significantly throughout the disease. Its high expression level is correlated with positive prognostic value. Based on this study, if the range of detection indicators is expanded, the sample size is increased, and the follow-up time is increased, miRNAs and their target genes would have significant differences in expression in the blood and bone marrow of MM patients from onset to complete remission before and after treatment.
In summary, different types of ncRNAs functions in proliferation, apoptosis, angiogenesis, immune escape, osteoclastogenesis, and drug resistance, affecting various aspects of MM occurrence, development, treatment, and prognosis (Fig. 2 ). Finding differentially expressed ncRNAs could bring unexpected therapeutic effects on MM treatment. Fig. 2 Mechanisms of ncRNA in multiple myeloma progression and therapy. ncRNA Types (green boxes): lncRNA, circRNA, miRNA. Key RNA names (orange boxes): lncRNA include NEAT1, CATG00000112921.1, NORAD, FEZF1-AS1, NBR2, MALAT1 and H19. circRNA include Circ_0005615, circ_0001821, circRFWD_2369aa and circCCT3. miRNA include miR-26, miR-1179, miR-140-5p, miR-28-3p, miR-34a, miR-223-3p, miR-16, miR-21 and miR-182. Intervention mechanism and approach (blue boxes): Immune escape, diagnosis, apoptosis, progress, proliferation, migration, osteoclast differentiation, cell development, apoptosis, drug resistance, prognosis and transfer
It should be noted that MM is a heterogeneous disease, with significant differences in ncRNA expression profiles among patients. In the future, it may be necessary to adopt personalized medicine approaches, tailoring treatment plans based on individual ncRNA expression profiles to enhance therapeutic efficacy. The primary research directions moving forward should focus on high-throughput sequencing and bioinformatics analysis to precisely identify the direct target genes of ncRNAs, thereby reducing off-target effects. Additionally, expanding the sample size to understand the ncRNA expression profiles and genetic heterogeneity in different MM patients is essential for developing personalized treatment strategies. Integrating the efforts of multiple disciplines, including oncology, molecular biology, pharmacology, and clinical medicine, will be crucial for advancing the clinical treatment of MM based on miRNA.
Relationship between m6A modification and ncRNA
Relationship between m6A modification and circRNA
Abnormalities in enzymes involved in m6A modification can cause a series of diseases. In recent years, the number of studies on m6A modification of ncRNAs has increased and gradually taken shape, but further in-depth mechanistic research is needed. Most circRNAs are located in the cytoplasm, and those containing introns are often found in the nucleus. Therefore, regulating the nuclear output of circRNAs is necessary. Previous studies have shown that YTHDC1, as a type of m6A reading protein, can affect the nuclear output of circRNA3634 [ 65 ]. Therefore, further study on m6A modification in circRNA may bring new inside into circRNA regulation.
M6A modification plays a crucial role in various aspects of circRNA metabolism. The hsa_circRNA_103820 regulated by m6A reader IGF2BP3 can inhibit the malignant progression of lung cancer cells [ 66 ]. Lowering the expression of circKEAP1 through m6A modification can promote the stemness, proliferation, and migration of osteosarcoma cells [ 39 ]. Lowering the expression of circ_1124554 can also promote the progression of rectal cancer [ 67 ]. In summary, m6A modification can regulate circRNA expression and function through various mechanisms, including affecting their subcellular localization, stability, and interactions with RNA-binding proteins or miRNAs. Further understanding of the m6A-circRNA axis and its impact on disease progression in MM could shed light on finding new therapeutic targets and biomarkers for this disease.
Relationship between m6A modification and lncRNA
The m6A modification of lncRNA can promote tumor progression. For example, m6A methyltransferase ZCCHC4 downregulates LncRNAGHRLOS to promote proliferation, migration, and invasion of colorectal cancer cells [ 68 ], and METTL14 can promote the progression of non-small cell carcinoma by upregulating MSTRG.292666.16 and increasing its m6A modification level [ 69 ]. The above research confirm that inhibit m6A modification of lncRNA may affect disease progression, providing new targets for disease diagnosis and treatment.
On the other hand, m6A modification of lncRNA can also inhibit disease progression and prevent disease occurrence. For example, m6A methyltransferase ZC3H13 can stabilize lncRNA A1BG-AS1, thereby preventing malignant tumors of prostate cancer cells [ 70 ], while METTL3 stabilizes LINC00894 in an m6A-dependent manner to inhibit the progression of thyroid cancer and lymph node metastasis, reducing the degree of tumor malignancy [ 71 ]. And the interaction between lncRNA FOXM1 and ALKBH5 disrupts the tumorigenesis of glioblastoma [ 72 ]. In MM, lncRNAs have been shown to interact with key signaling pathways and transcription factors, influencing disease progression. For instance, lncRNA FEZF1-AS1 can accelerate MM progression by interacting with the IGF2BP1/BZW2 signaling pathway [ 50 ]. Specifically, FEZF1-AS1 stabilizes IGF2BP1 mRNA through m6A modification, enhancing its translation and subsequent activation of the BZW2 pathway, which promotes MM cell proliferation and survival. Targeting this lncRNA or its interaction with IGF2BP1 could be a potential therapeutic strategy.
Based on these studies, it can be inferred that by regulating the expression levels of m6A-related proteins, lncRNA expression can be controlled, ultimately creating a positive impact on disease treatment. This can range from preventing tumor occurrence, inhibiting tumor cell metastasis, and disrupting tumor cell generation.
Relationship between m6A modification and miRNA
As mentioned earlier, we have found that in MM, specific miRNAs, influenced by m6A modification, play crucial roles in regulating cell proliferation, apoptosis, and drug resistance [ 58 , 60 , 61 ]. The m6A modification of miRNA affect various biological processes and significantly affect inflammation and tumors. For example, the enrichment of miR-193a induced by m6A modification plays an important regulatory role in the inflammatory response of myocardial cells in septic cardiomyopathy [ 73 ]. Secondly, reducing m6A modification and miR-140-3p binding can lead to the upregulation of BET1L to promote colorectal cancer tumorigenesis [ 74 ]. Finally, M6A methyltransferase METTL3-mediated m6A modification can upregulate miR-19a-3p, thereby promoting the proliferation and invasion of nasopharyngeal carcinoma cells and driving their progression [ 75 ]. These research provide evidence for the rational to intervene m6A modification of miRNA to prevent the onset and development of various diseases.
In summary, m6A modification can interact with various ncRNAs and regulate expression of m6A-related proteins such as YTHDC1, IGF2BP3, METTL3, and ALKBH5. It can affect cell proliferation, invasion, metastasis, and inflammatory response of various cancers, thereby affecting the onset and treatment of diseases (Fig. 3 ). Among them, the role of METTL3 has been studied extensively and solidified its role in the progression and metastasis of different cancers. However, it is important to note the potential limitations of these studies. For instance, the findings are often based on in vitro experiments and may not fully reflect the complexity of the tumor microenvironment in vivo. Additionally, the targeting of miRNAs can have off-target effects, which may complicate the interpretation of results and the development of miRNA-based therapies. Therefore, further research is needed to validate these findings in clinical settings and to develop strategies to minimize off-target effects. Fig. 3 Crosstalk between m6A modification and ncRNA in cancer pathogenesis. Methylase type (green boxes): methyltransferase, demethylase, methylated reading protein. Core Regulatory Proteins (orange boxes): METTL3, METTL14, ZCCHC4, ZCCHC13, ALKBH5, YTHDC1, IGF2BP3. Associated nc RNA (blue boxes): miR-19a-3p, LINC00894, MSTRG.292666.16, LncRNA GHRLOS, lncRNA A1BG-AS1, lncRNA FOXM1, circRNA nuclear export, circRNA_103820
In summary, m6A modification can interact with various ncRNAs, and regulate the expression of m6A-related proteins such as YTHDC1, IGF2BP3, METTL3, and ALKBH5. These interactions can affect cell proliferation, invasion, metastasis, and inflammatory responses in various cancers, thereby influencing disease onset and treatment outcomes. While the role of METTL3 in cancer progression and metastasis has been extensively studied, further research is needed to elucidate the specific mechanisms by which m6A modification of miRNA influences MM progression and to develop targeted therapies that can overcome the limitations of current approaches.
m6A modification intervenes in the progression of multiple myeloma by intervening in ncRNA
In summary, m6A modification is closely related to ncRNA. m6A modification can regulate ncRNA through various pathways, ultimately affecting disease progression. For example, m6A methyltransferase METTL3 upregulates PTCH1 expression by enhancing PTCH1 m6A modification, thereby promoting the growth and stemness of esophageal cancer cells [ 76 ]. This not only confirms that m6A modification regulates ncRNA intervention in disease progression but once again confirm the promising therapeutics strategy of this m6A modification-ncRNA regulation.
Research has found that bone homeostasis imbalance is one of the causes of MM, and MM patients are often accompanied by inhibited osteoblast activity and excessive osteoclastogenesis [ 77 ]. Methyltransferase METTL3 can promote osteoblast differentiation by increasing the m6A modification level of the circuit [ 78 ], while miR-615-3p can also regulate the m6A reading protein YTHDF2 to promote the function of FBLN1, thereby affecting the osteogenic differentiation of umbilical cord blood mesenchymal stem cells [ 79 ]. HnRNPA2B1 in MM cells can upregulate the expression of miR-92a-5p and miR-373-3p, thereby activating osteoclastogenesis and inhibiting osteoblast generation [ 80 ]. Therefore, m6A modification may be closely related to the progression of MM and may affect the progression of MM by regulating the activity of osteoblasts and osteoclasts. These findings confirm that m6A modification can regulate ncRNA, which can inhibit MM progression, improve patient quality of life. and serve as possible methods to prevent MM.
Many studies indirectly or directly confirmed m6A modification can regulate ncRNA in multiple myeloma. For example, METTL3 can regulate miRNA expression and affect the development of multiple myeloma [ 21 ]. Experimental verification has also found that ALKBH5 upregulates and stabilizes lncRNA SNHG15, which is elevated in MM [ 81 ]. Therefore, ALKBH5 regulation on SNHG15 expression plays an important role in disease progression. However, there are still significant research gaps in understanding the relationship between m6A modification and ncRNA in MM, which necessitates further investigation by the research community. This review provides some insights for plausible future research directions.
Conclusion
There have been many studies on the relationship between m6A modification and ncRNA intervention in the occurrence, development, and prognosis of multiple myeloma, which discovered throughout various stages of the disease. However, direct evidence that m6A modification intervenes in multiple myeloma by regulating ncRNA is still lacking. Based on the existing research, we speculate that there may be three possible therapeutics methods. First, knocking down ALKBH5 expression can affect ncRNA expression, promote MM cell apoptosis, and thus halt MM growth. Second is to inhibit ncRNA expression by reducing METTL3 expression, subsequently reducing osteoclast differentiation, and promoting osteoblast generation, thereby reducing the progression of disease. Lastly, by reducing the expression of FTO and thus controlling the expression of ncRNA, thereby reducing the resistance of MM patients to existing drugs, improving drug efficacy, and increasing patient survival. Further research on these three approaches may provide promising methods for the diagnosis, treatment, and prognosis of multiple myeloma. However, there are still some difficulties in the clinical application of these methods. They can be overcome by developing highly specific inhibitors to reduce off-target effects, optimizing delivery systems to overcome bone marrow microenvironment barriers, and stratifying patients with biomarkers to enhance treatment response rates. Future research can utilize single-cell sequencing and organoid models to explore how MM heterogeneity impacts the m6A-ncRNA network and to investigate the synergistic effects of combination therapies.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Author contributions
All authors contributed to the study. The article topic was selected by [ZHOU Yongming] and [CHEN Hailin]. The literature collection was performed by [ZHU Wenwei]. The first draft of the manuscript was written by [SUN Xiaoqi] and all authors commented on previous versions of the manuscript. All authors read and approved the final.
Funding
This work was supported by [Construction Project of National Famous Traditional Chinese Medicine Expert Inheritance Studio by the State Administration of Traditional Chinese Medicine. Shanghai Clinical Key Specialty Construction Project. High level Key Discipline Construction Project of Traditional Chinese Medicine of the State Administration of Traditional Chinese Medicine. Peak Plateau Team Project of Shanghai University of Traditional Chinese Medicine. Shanghai Famous Traditional Chinese Medicine Academic Experience Research Studio Construction Project. Shanghai Baiyulan Talent Plan Pujiang Project. (Grant numbers [National Medical Education Letter [2022] No. 75] [shslczdzk05201] [zyyzdxk-202365] [30304114341] [SHGZS-2017019] and [23PJD095]).
Data availability
No datasets were generated or analysed during the current study.
Declarations
Ethics approval and consent to participate
The authors have no relevant financial or non-financial interests to disclose.
Conflict of interest
The authors declare no competing interests.
References
1. Bao J Xu T Wang W Xu H Chen X Xia R N6-methyladenosine-induced mir-182-5p promotes multiple myeloma tumorigenesis by regulating camk2n1 Mol Cell Biochem 2024 10.1007/s11010-023-04906-w 38180718 Bao J, Xu T, Wang W, Xu H, Chen X, Xia R. N6-methyladenosine-induced mir-182-5p promotes multiple myeloma tumorigenesis by regulating camk2n1. Mol Cell Biochem. 2024. 10.1007/s11010-023-04906-w. 38180718 10.1007/s11010-023-04906-w
2. Crespo-Garcia E Bueno-Costa A Esteller M Single-cell analysis of the epitranscriptome: rna modifications under the microscope RNA Biol 2024 21 1 1 8 10.1080/15476286.2024.2315385 38368619 PMC10877985 Crespo-Garcia E, Bueno-Costa A, Esteller M. Single-cell analysis of the epitranscriptome: rna modifications under the microscope. RNA Biol. 2024;21(1):1–8. 10.1080/15476286.2024.2315385. 38368619 10.1080/15476286.2024.2315385 PMC10877985
3. Erson-Bensan AE Begik O M6a modification and implications for micrornas Microrna 2017 6 2 97 101 10.2174/2211536606666170511102219 28494721 Erson-Bensan AE, Begik O. M6a modification and implications for micrornas. Microrna. 2017;6(2):97–101. 10.2174/2211536606666170511102219. 28494721 10.2174/2211536606666170511102219
4. Qiu X Chen D Huang S Chen N Wu J Liang S Peng P Qin M Huang J Liu S Identification and verification of m6a-related mirnas correlated with prognosis and immune microenvironment in colorectal cancer Medicine (Baltimore) 2023 102 46 e35984 10.1097/MD.0000000000035984 37986290 PMC10659607 Qiu X, Chen D, Huang S, Chen N, Wu J, Liang S, Peng P, Qin M, Huang J, Liu S. Identification and verification of m6a-related mirnas correlated with prognosis and immune microenvironment in colorectal cancer. Medicine (Baltimore). 2023;102(46):e35984. 10.1097/MD.0000000000035984. 37986290 10.1097/MD.0000000000035984 PMC10659607
5. Yang Z Jiang X Zhang Z Zhao Z Xing W Liu Y Jiang X Zhao H Hdac3-dependent transcriptional repression of foxa2 regulates fto/m6a/myc signaling to contribute to the development of gastric cancer Cancer Gene Ther 2021 28 1–2 141 155 10.1038/s41417-020-0193-8 32655129 Yang Z, Jiang X, Zhang Z, Zhao Z, Xing W, Liu Y, Jiang X, Zhao H. Hdac3-dependent transcriptional repression of foxa2 regulates fto/m6a/myc signaling to contribute to the development of gastric cancer. Cancer Gene Ther. 2021;28(1–2):141–55. 10.1038/s41417-020-0193-8. 32655129 10.1038/s41417-020-0193-8
6. Wang Y Bin T Tang J Xu XJ Lin C Lu B Sun TT Construction of an acute myeloid leukemia prognostic model based on m6a-related efferocytosis-related genes Front Immunol 2023 14 1268090 10.3389/fimmu.2023.1268090 38077322 PMC10704160 Wang Y, Bin T, Tang J, Xu XJ, Lin C, Lu B, Sun TT. Construction of an acute myeloid leukemia prognostic model based on m6a-related efferocytosis-related genes. Front Immunol. 2023;14:1268090. 10.3389/fimmu.2023.1268090. 38077322 10.3389/fimmu.2023.1268090 PMC10704160
7. Li J Zhu Z Zhu Y Li J Li K Zhong W Mettl3-mediated m6a methylation of c1qa regulates the rituximab resistance of diffuse large b-cell lymphoma cells Cell Death Discov 2023 9 1 405 10.1038/s41420-023-01698-2 37907575 PMC10618261 Li J, Zhu Z, Zhu Y, Li J, Li K, Zhong W. Mettl3-mediated m6a methylation of c1qa regulates the rituximab resistance of diffuse large b-cell lymphoma cells. Cell Death Discov. 2023;9(1):405. 10.1038/s41420-023-01698-2. 37907575 10.1038/s41420-023-01698-2 PMC10618261
8. Jia Y Yu X Liu R Shi L Jin H Yang D Zhang X Shen Y Feng Y Zhang P Yang Y Zhang L Zhang P Li Z He A Kong G Prmt1 methylation of wtap promotes multiple myeloma tumorigenesis by activating oxidative phosphorylation via m6a modification of ndufs6 Cell Death Dis 2023 14 8 512 10.1038/s41419-023-06036-z 37558663 PMC10412649 Jia Y, Yu X, Liu R, Shi L, Jin H, Yang D, Zhang X, Shen Y, Feng Y, Zhang P, Yang Y, Zhang L, Zhang P, Li Z, He A, Kong G. Prmt1 methylation of wtap promotes multiple myeloma tumorigenesis by activating oxidative phosphorylation via m6a modification of ndufs6. Cell Death Dis. 2023;14(8):512. 10.1038/s41419-023-06036-z. 37558663 10.1038/s41419-023-06036-z PMC10412649
9. Wu Y Luo Y Yao X Shi X Xu Z Re J Shi M Li M Liu J He Y Du X Kiaa1429 increases foxm1 expression through ythdf1-mediated m6a modification to promote aerobic glycolysis and tumorigenesis in multiple myeloma Cell Biol Toxicol 2024 40 1 58 10.1007/s10565-024-09904-2 39060874 PMC11282141 Wu Y, Luo Y, Yao X, Shi X, Xu Z, Re J, Shi M, Li M, Liu J, He Y, Du X. Kiaa1429 increases foxm1 expression through ythdf1-mediated m6a modification to promote aerobic glycolysis and tumorigenesis in multiple myeloma. Cell Biol Toxicol. 2024;40(1):58. 10.1007/s10565-024-09904-2. 39060874 10.1007/s10565-024-09904-2 PMC11282141
10. Huang X Yang Z Li Y Long X M6a methyltransferase mettl3 facilitates multiple myeloma cell growth through the m6a modification of bzw2 Ann Hematol 2023 102 7 1801 1810 10.1007/s00277-023-05283-6 37222774 Huang X, Yang Z, Li Y, Long X. M6a methyltransferase mettl3 facilitates multiple myeloma cell growth through the m6a modification of bzw2. Ann Hematol. 2023;102(7):1801–10. 10.1007/s00277-023-05283-6. 37222774 10.1007/s00277-023-05283-6
11. Zhu K Gou F Zhao Z Xu K Song J Jiang H Zhang F Yang Y Li J Circ_0005615 enhances multiple myeloma progression through interaction with eif4a3 to regulate map3k4 m6a modification mediated by alkbh5 Leuk Res 2024 141 107451 10.1016/j.leukres.2024.107451 38663164 Zhu K, Gou F, Zhao Z, Xu K, Song J, Jiang H, Zhang F, Yang Y, Li J. Circ_0005615 enhances multiple myeloma progression through interaction with eif4a3 to regulate map3k4 m6a modification mediated by alkbh5. Leuk Res. 2024;141:107451. 10.1016/j.leukres.2024.107451. 38663164 10.1016/j.leukres.2024.107451
12. Xu J Wang Y Ren L Li P Liu P Igf2bp1 promotes multiple myeloma with chromosome 1q gain via increasing cdc5l expression in an m(6)a-dependent manner Genes Dis 2025 12 1 101214 10.1016/j.gendis.2024.101214 39534570 PMC11554607 Xu J, Wang Y, Ren L, Li P, Liu P. Igf2bp1 promotes multiple myeloma with chromosome 1q gain via increasing cdc5l expression in an m(6)a-dependent manner. Genes Dis. 2025;12(1):101214. 10.1016/j.gendis.2024.101214. 39534570 10.1016/j.gendis.2024.101214 PMC11554607
13. Jiang S Gao L Li J Zhang F Zhang Y Liu J N6-methyladenosine-modified circ_0000337 sustains bortezomib resistance in multiple myeloma by regulating dna repair Front Cell Dev Biol 2024 12 1383232 10.3389/fcell.2024.1383232 38586304 PMC10995360 Jiang S, Gao L, Li J, Zhang F, Zhang Y, Liu J. N6-methyladenosine-modified circ_0000337 sustains bortezomib resistance in multiple myeloma by regulating dna repair. Front Cell Dev Biol. 2024;12:1383232. 10.3389/fcell.2024.1383232. 38586304 10.3389/fcell.2024.1383232 PMC10995360
14. Lin S Choe J Du P Triboulet R Gregory RI The m(6)a methyltransferase mettl3 promotes translation in human cancer cells Mol Cell 2016 62 3 335 345 10.1016/j.molcel.2016.03.021 27117702 PMC4860043 Lin S, Choe J, Du P, Triboulet R, Gregory RI. The m(6)a methyltransferase mettl3 promotes translation in human cancer cells. Mol Cell. 2016;62(3):335–45. 10.1016/j.molcel.2016.03.021. 27117702 10.1016/j.molcel.2016.03.021 PMC4860043
15. Zhou W Li S Wang H Zhou J Li S Chen G Guan W Fu X Nervi C Yu L Li Y A novel aml1-eto/fto positive feedback loop promotes leukemogenesis and ara-c resistance via stabilizing igfbp2 in t(8;21) acute myeloid leukemia Exp Hematol Oncol 2024 13 1 9 10.1186/s40164-024-00480-z 38268050 PMC10807068 Zhou W, Li S, Wang H, Zhou J, Li S, Chen G, Guan W, Fu X, Nervi C, Yu L, Li Y. A novel aml1-eto/fto positive feedback loop promotes leukemogenesis and ara-c resistance via stabilizing igfbp2 in t(8;21) acute myeloid leukemia. Exp Hematol Oncol. 2024;13(1):9. 10.1186/s40164-024-00480-z. 38268050 10.1186/s40164-024-00480-z PMC10807068
16. Mei Z Shen Z Pu J Liu Q Liu G He X Wang Y Yue J Ge S Li T Yuan Y Yang L Nat10 mediated ac4c acetylation driven m(6)a modification via involvement of ythdc1-ldha/pfkm regulates glycolysis and promotes osteosarcoma Cell Commun Signal 2024 22 1 51 10.1186/s12964-023-01321-y 38233839 PMC10795323 Mei Z, Shen Z, Pu J, Liu Q, Liu G, He X, Wang Y, Yue J, Ge S, Li T, Yuan Y, Yang L. Nat10 mediated ac4c acetylation driven m(6)a modification via involvement of ythdc1-ldha/pfkm regulates glycolysis and promotes osteosarcoma. Cell Commun Signal. 2024;22(1):51. 10.1186/s12964-023-01321-y. 38233839 10.1186/s12964-023-01321-y PMC10795323
17. Yang R Yang C Su D Song Y Min J Qian Z Shen X Li J Su H Mettl3-mediated rangap1 promotes colorectal cancer progression through the mapk pathway by recruiting ythdf1 Cancer Gene Ther 2024 10.1038/s41417-024-00731-5 38267624 PMC11016466 Yang R, Yang C, Su D, Song Y, Min J, Qian Z, Shen X, Li J, Su H. Mettl3-mediated rangap1 promotes colorectal cancer progression through the mapk pathway by recruiting ythdf1. Cancer Gene Ther. 2024. 10.1038/s41417-024-00731-5. 38267624 10.1038/s41417-024-00731-5 PMC11016466
18. Jiang J Zhu J Qiu P Ni J Zhu W Wang X Hnrnpa2b1-mediated m6a modification of foxm1 promotes drug resistance and inhibits ferroptosis in endometrial cancer via regulation of lcn2 Funct Integr Genomics 2023 24 1 3 10.1007/s10142-023-01279-7 38091112 Jiang J, Zhu J, Qiu P, Ni J, Zhu W, Wang X. Hnrnpa2b1-mediated m6a modification of foxm1 promotes drug resistance and inhibits ferroptosis in endometrial cancer via regulation of lcn2. Funct Integr Genomics. 2023;24(1):3. 10.1007/s10142-023-01279-7. 38091112 10.1007/s10142-023-01279-7
19. Jin J Fu L Hong P Feng W Malat-1 regulates the aml progression by promoting the m6a modification of zeb1 Acta Biochim Pol 2023 70 1 37 43 10.18388/abp.2020_6017 36812496 Jin J, Fu L, Hong P, Feng W. Malat-1 regulates the aml progression by promoting the m6a modification of zeb1. Acta Biochim Pol. 2023;70(1):37–43. 10.18388/abp.2020_6017. 36812496 10.18388/abp.2020_6017
20. Wang L Yi X Xiao X Zheng Q Ma L Li B Exosomal mir-628-5p from m1 polarized macrophages hinders m6a modification of circfut8 to suppress hepatocellular carcinoma progression Cell Mol Biol Lett 2022 27 1 106 10.1186/s11658-022-00406-9 36474147 PMC9724320 Wang L, Yi X, Xiao X, Zheng Q, Ma L, Li B. Exosomal mir-628-5p from m1 polarized macrophages hinders m6a modification of circfut8 to suppress hepatocellular carcinoma progression. Cell Mol Biol Lett. 2022;27(1):106. 10.1186/s11658-022-00406-9. 36474147 10.1186/s11658-022-00406-9 PMC9724320
21. Che F Ye X Wang Y Wang X Ma S Tan Y Mao Y Luo Z Mettl3 facilitates multiple myeloma tumorigenesis by enhancing yy1 stability and pri-microrna-27 maturation in m(6)a-dependent manner Cell Biol Toxicol 2023 39 5 2033 2050 10.1007/s10565-021-09690-1 35038059 Che F, Ye X, Wang Y, Wang X, Ma S, Tan Y, Mao Y, Luo Z. Mettl3 facilitates multiple myeloma tumorigenesis by enhancing yy1 stability and pri-microrna-27 maturation in m(6)a-dependent manner. Cell Biol Toxicol. 2023;39(5):2033–50. 10.1007/s10565-021-09690-1. 35038059 10.1007/s10565-021-09690-1
22. Chen CJ Huang JY Huang JQ Deng JY Shangguan XH Chen AZ Chen LT Wu WH Metformin attenuates multiple myeloma cell proliferation and encourages apoptosis by suppressing mettl3-mediated m6a methylation of thrap3, rbm25, and usp4 Cell Cycle 2023 22 8 986 1004 10.1080/15384101.2023.2170521 36762777 PMC10054227 Chen CJ, Huang JY, Huang JQ, Deng JY, Shangguan XH, Chen AZ, Chen LT, Wu WH. Metformin attenuates multiple myeloma cell proliferation and encourages apoptosis by suppressing mettl3-mediated m6a methylation of thrap3, rbm25, and usp4. Cell Cycle. 2023;22(8):986–1004. 10.1080/15384101.2023.2170521. 36762777 10.1080/15384101.2023.2170521 PMC10054227
23. Wei R Cao Y Wu H Liu X Jiang M Luo X Deng Z Wang Z Ke M Zhu Y Chen S Gu C Yang Y Inhibition of vcp modulates nf-kappab signaling pathway to suppress multiple myeloma cell proliferation and osteoclast differentiation Aging (Albany NY) 2023 15 16 8220 8236 10.18632/aging.204965 37606987 PMC10497005 Wei R, Cao Y, Wu H, Liu X, Jiang M, Luo X, Deng Z, Wang Z, Ke M, Zhu Y, Chen S, Gu C, Yang Y. Inhibition of vcp modulates nf-kappab signaling pathway to suppress multiple myeloma cell proliferation and osteoclast differentiation. Aging (Albany NY). 2023;15(16):8220–36. 10.18632/aging.204965. 37606987 10.18632/aging.204965 PMC10497005
24. Li X Fan C Wang J Li P Xu X Guo R Wei J Cheng Y Lin H Fu X Follicle-stimulating hormone accelerates osteoclast migration by enhancing methyltransferase-like 3-mediated m6a methylation of cathepsin k J Mol Endocrinol 2024 10.1530/JME-23-0130 38261314 Li X, Fan C, Wang J, Li P, Xu X, Guo R, Wei J, Cheng Y, Lin H, Fu X. Follicle-stimulating hormone accelerates osteoclast migration by enhancing methyltransferase-like 3-mediated m6a methylation of cathepsin k. J Mol Endocrinol. 2024. 10.1530/JME-23-0130. 38261314 10.1530/JME-23-0130
25. Xu A Zhang J Zuo L Yan H Chen L Zhao F Fan F Xu J Zhang B Zhang Y Yin X Cheng Q Gao S Deng J Mei H Huang Z Sun C Hu Y Fto promotes multiple myeloma progression by posttranscriptional activation of hsf1 in an m(6)a-ythdf2-dependent manner Mol Ther 2022 30 3 1104 1118 10.1016/j.ymthe.2021.12.012 34915192 PMC8899603 Xu A, Zhang J, Zuo L, Yan H, Chen L, Zhao F, Fan F, Xu J, Zhang B, Zhang Y, Yin X, Cheng Q, Gao S, Deng J, Mei H, Huang Z, Sun C, Hu Y. Fto promotes multiple myeloma progression by posttranscriptional activation of hsf1 in an m(6)a-ythdf2-dependent manner. Mol Ther. 2022;30(3):1104–18. 10.1016/j.ymthe.2021.12.012. 34915192 10.1016/j.ymthe.2021.12.012 PMC8899603
26. Wang C Li L Li M Wang W Jiang Z Fto promotes bortezomib resistance via m6a-dependent destabilization of sod2 expression in multiple myeloma Cancer Gene Ther 2023 30 4 622 628 10.1038/s41417-022-00429-6 35145273 Wang C, Li L, Li M, Wang W, Jiang Z. Fto promotes bortezomib resistance via m6a-dependent destabilization of sod2 expression in multiple myeloma. Cancer Gene Ther. 2023;30(4):622–8. 10.1038/s41417-022-00429-6. 35145273 10.1038/s41417-022-00429-6
27. Yu T Yao L Yin H Teng Y Hong M Wu Q Alkbh5 promotes multiple myeloma tumorigenicity through inducing m(6)a-demethylation of sav1 mrna and myeloma stem cell phenotype Int J Biol Sci 2022 18 6 2235 2248 10.7150/ijbs.64943 35414790 PMC8990482 Yu T, Yao L, Yin H, Teng Y, Hong M, Wu Q. Alkbh5 promotes multiple myeloma tumorigenicity through inducing m(6)a-demethylation of sav1 mrna and myeloma stem cell phenotype. Int J Biol Sci. 2022;18(6):2235–48. 10.7150/ijbs.64943. 35414790 10.7150/ijbs.64943 PMC8990482
28. Qu J Hou Y Chen Q Chen J Li Y Zhang E Gu H Xu R Liu Y Cao W Zhang J Cao L He J Cai Z Rna demethylase alkbh5 promotes tumorigenesis in multiple myeloma via traf1-mediated activation of nf-kappab and mapk signaling pathways Oncogene 2022 41 3 400 413 10.1038/s41388-021-02095-8 34759347 PMC8755544 Qu J, Hou Y, Chen Q, Chen J, Li Y, Zhang E, Gu H, Xu R, Liu Y, Cao W, Zhang J, Cao L, He J, Cai Z. Rna demethylase alkbh5 promotes tumorigenesis in multiple myeloma via traf1-mediated activation of nf-kappab and mapk signaling pathways. Oncogene. 2022;41(3):400–13. 10.1038/s41388-021-02095-8. 34759347 10.1038/s41388-021-02095-8 PMC8755544
29. Jia C Guo Y Chen Y Wang X Xu Q Zhang Y Quan L Hnrnpa2b1-mediated m6a modification of tlr4 mrna promotes progression of multiple myeloma J Transl Med 2022 20 1 537 10.1186/s12967-022-03750-8 36401285 PMC9673362 Jia C, Guo Y, Chen Y, Wang X, Xu Q, Zhang Y, Quan L. Hnrnpa2b1-mediated m6a modification of tlr4 mrna promotes progression of multiple myeloma. J Transl Med. 2022;20(1):537. 10.1186/s12967-022-03750-8. 36401285 10.1186/s12967-022-03750-8 PMC9673362
30. Jiang F Tang X Tang C Hua Z Ke M Wang C Zhao J Gao S Jurczyszyn A Janz S Beksac M Zhan F Gu C Yang Y Hnrnpa2b1 promotes multiple myeloma progression by increasing akt3 expression via m6a-dependent stabilization of ilf3 mrna J Hematol Oncol 2021 14 1 54 10.1186/s13045-021-01066-6 33794982 PMC8017865 Jiang F, Tang X, Tang C, Hua Z, Ke M, Wang C, Zhao J, Gao S, Jurczyszyn A, Janz S, Beksac M, Zhan F, Gu C, Yang Y. Hnrnpa2b1 promotes multiple myeloma progression by increasing akt3 expression via m6a-dependent stabilization of ilf3 mrna. J Hematol Oncol. 2021;14(1):54. 10.1186/s13045-021-01066-6. 33794982 10.1186/s13045-021-01066-6 PMC8017865
31. Liu R Miao J Jia Y Kong G Hong F Li F Zhai M Zhang R Liu J Xu X Wang T Liu H Hu J Yang Y He A N6-methyladenosine reader ythdf2 promotes multiple myeloma cell proliferation through egr1/p21(cip1/waf1)/cdk2-cyclin e1 axis-mediated cell cycle transition Oncogene 2023 42 20 1607 1619 10.1038/s41388-023-02675-w 37012388 PMC10181929 Liu R, Miao J, Jia Y, Kong G, Hong F, Li F, Zhai M, Zhang R, Liu J, Xu X, Wang T, Liu H, Hu J, Yang Y, He A. N6-methyladenosine reader ythdf2 promotes multiple myeloma cell proliferation through egr1/p21(cip1/waf1)/cdk2-cyclin e1 axis-mediated cell cycle transition. Oncogene. 2023;42(20):1607–19. 10.1038/s41388-023-02675-w. 37012388 10.1038/s41388-023-02675-w PMC10181929
32. Wang J Zuo Y Lv C Zhou M Wan Y N6-methyladenosine regulators are potential prognostic biomarkers for multiple myeloma IUBMB Life 2023 75 2 137 148 10.1002/iub.2678 36177774 PMC10115423 Wang J, Zuo Y, Lv C, Zhou M, Wan Y. N6-methyladenosine regulators are potential prognostic biomarkers for multiple myeloma. IUBMB Life. 2023;75(2):137–48. 10.1002/iub.2678. 36177774 10.1002/iub.2678 PMC10115423
33. Song S Fan G Li Q Su Q Zhang X Xue X Wang Z Qian C Jin Z Li B Zhuang W Idh2 contributes to tumorigenesis and poor prognosis by regulating m6a rna methylation in multiple myeloma Oncogene 2021 40 35 5393 5402 10.1038/s41388-021-01939-7 34274946 Song S, Fan G, Li Q, Su Q, Zhang X, Xue X, Wang Z, Qian C, Jin Z, Li B, Zhuang W. Idh2 contributes to tumorigenesis and poor prognosis by regulating m6a rna methylation in multiple myeloma. Oncogene. 2021;40(35):5393–402. 10.1038/s41388-021-01939-7. 34274946 10.1038/s41388-021-01939-7
34. Ramasamy D Thippannah M Maharajan H Balaiah M Seshadri RA Kodous AS Herceg Z Mehta A Rao A Mani S Transcriptome-wide profiling identifies colon cancer-associated m6a transcripts and potential rna methyl modifiers Mol Biol Rep 2024 51 1 299 10.1007/s11033-024-09217-x 38345740 Ramasamy D, Thippannah M, Maharajan H, Balaiah M, Seshadri RA, Kodous AS, Herceg Z, Mehta A, Rao A, Mani S. Transcriptome-wide profiling identifies colon cancer-associated m6a transcripts and potential rna methyl modifiers. Mol Biol Rep. 2024;51(1):299. 10.1007/s11033-024-09217-x. 38345740 10.1007/s11033-024-09217-x
35. Men X Hu A Xu T Circlzic regulates ox-ldl-induced huvec cell proliferation and apoptosis via micro-330-5p/notch2 axis in atherosclerosis Clin Hemorheol Microcirc 2024 10.3233/CH-232063 38277288 PMC11191521 Men X, Hu A, Xu T. Circlzic regulates ox-ldl-induced huvec cell proliferation and apoptosis via micro-330-5p/notch2 axis in atherosclerosis. Clin Hemorheol Microcirc. 2024. 10.3233/CH-232063. 38277288 10.3233/CH-232063 PMC11191521
36. Zhou H Wu R Li H Silencing circldlrad3 inhibits lung cancer progression by regulating the mir-497-5p/pfkp axis Mol Biotechnol 2024 10.1007/s12033-024-01047-3 38427179 Zhou H, Wu R, Li H. Silencing circldlrad3 inhibits lung cancer progression by regulating the mir-497-5p/pfkp axis. Mol Biotechnol. 2024. 10.1007/s12033-024-01047-3. 38427179 10.1007/s12033-024-01047-3
37. Zhang W Yang Q Qian D Zhao K Tang C Ju S Deregulation of circrna hsa_circ_0009109 promotes tumor growth and initiates autophagy by sponging mir-544a-3p in gastric cancer Gastroenterol Rep (Oxf) 2024 10.1093/gastro/goae008 38425655 PMC10902679 Zhang W, Yang Q, Qian D, Zhao K, Tang C, Ju S. Deregulation of circrna hsa_circ_0009109 promotes tumor growth and initiates autophagy by sponging mir-544a-3p in gastric cancer. Gastroenterol Rep (Oxf). 2024. 10.1093/gastro/goae008. 38425655 10.1093/gastro/goae008 PMC10902679
38. Wei Z Zhang C Song Y Han D Liu J Song X Chao F Wang S Xu G Chen G Circube3a(2,3,4,5) promotes adenylate-uridylate-rich binding factor 1 nuclear translocation to suppress prostate cancer metastasis Cancer Lett 2024 588 216743 10.1016/j.canlet.2024.216743 38423246 Wei Z, Zhang C, Song Y, Han D, Liu J, Song X, Chao F, Wang S, Xu G, Chen G. Circube3a(2,3,4,5) promotes adenylate-uridylate-rich binding factor 1 nuclear translocation to suppress prostate cancer metastasis. Cancer Lett. 2024;588:216743. 10.1016/j.canlet.2024.216743. 38423246 10.1016/j.canlet.2024.216743
39. Zhang Y Liu Z Zhong Z Ji Y Guo H Wang W Chen C A tumor suppressor protein encoded by circkeap1 inhibits osteosarcoma cell stemness and metastasis by promoting vimentin proteasome degradation and activating anti-tumor immunity J Exp Clin Cancer Res 2024 43 1 52 10.1186/s13046-024-02971-7 38383479 PMC10880370 Zhang Y, Liu Z, Zhong Z, Ji Y, Guo H, Wang W, Chen C. A tumor suppressor protein encoded by circkeap1 inhibits osteosarcoma cell stemness and metastasis by promoting vimentin proteasome degradation and activating anti-tumor immunity. J Exp Clin Cancer Res. 2024;43(1):52. 10.1186/s13046-024-02971-7. 38383479 10.1186/s13046-024-02971-7 PMC10880370
40. Zhou J Xu M Chen Z Huang L Wu Z Huang Z Liu L Circ_spef2 regulates the balance of treg cells by regulating mir-16-5p/bach2 in lymphoma and participates in the immune response Tissue Eng Regen Med 2023 20 7 1145 1159 10.1007/s13770-023-00585-2 37801226 PMC10645944 Zhou J, Xu M, Chen Z, Huang L, Wu Z, Huang Z, Liu L. Circ_spef2 regulates the balance of treg cells by regulating mir-16-5p/bach2 in lymphoma and participates in the immune response. Tissue Eng Regen Med. 2023;20(7):1145–59. 10.1007/s13770-023-00585-2. 37801226 10.1007/s13770-023-00585-2 PMC10645944
41. Tang YL Su JY Luo JS Zhang LD Zheng LM Liang C Wang LN Li Y Fan Z Huang DP Sun P Luo Z Qi NH Lan JJ Zhang XL Huang LB Luo XQ Gene expression network and circ_0008012 promote progression in mll/af4 positive acute lymphoblastic leukemia Recent Pat Anticancer Drug Discov 2023 18 4 538 548 10.2174/1574892818666221207115016 36503469 Tang YL, Su JY, Luo JS, Zhang LD, Zheng LM, Liang C, Wang LN, Li Y, Fan Z, Huang DP, Sun P, Luo Z, Qi NH, Lan JJ, Zhang XL, Huang LB, Luo XQ. Gene expression network and circ_0008012 promote progression in mll/af4 positive acute lymphoblastic leukemia. Recent Pat Anticancer Drug Discov. 2023;18(4):538–48. 10.2174/1574892818666221207115016. 36503469 10.2174/1574892818666221207115016
42. Zhang Q Duan H Yang W Liu H Tao X Zhang Y Circ_0005615 restrains the progression of multiple myeloma through modulating mir-331-3p and igf1r regulatory cascade J Orthop Surg Res 2023 18 1 356 10.1186/s13018-023-03832-3 37173768 PMC10176712 Zhang Q, Duan H, Yang W, Liu H, Tao X, Zhang Y. Circ_0005615 restrains the progression of multiple myeloma through modulating mir-331-3p and igf1r regulatory cascade. J Orthop Surg Res. 2023;18(1):356. 10.1186/s13018-023-03832-3. 37173768 10.1186/s13018-023-03832-3 PMC10176712
43. Liu L Zhang F Li J Circrna circ_0001821 predicts an unfavorable prognosis and promotes the proliferation of multiple myeloma Hematology 2021 26 1 716 723 10.1080/16078454.2021.1974199 34555307 Liu L, Zhang F, Li J. Circrna circ_0001821 predicts an unfavorable prognosis and promotes the proliferation of multiple myeloma. Hematology. 2021;26(1):716–23. 10.1080/16078454.2021.1974199. 34555307 10.1080/16078454.2021.1974199
44. Li F Liu J Miao J Hong F Liu R Lv Y Yang Y He A Wang J Circular rna circxpo1 promotes multiple myeloma progression by regulating mir-495-3p/dna damage-induced transcription 4 axis DNA Cell Biol 2024 43 1 39 55 10.1089/dna.2023.0288 38079253 PMC10825292 Li F, Liu J, Miao J, Hong F, Liu R, Lv Y, Yang Y, He A, Wang J. Circular rna circxpo1 promotes multiple myeloma progression by regulating mir-495-3p/dna damage-induced transcription 4 axis. DNA Cell Biol. 2024;43(1):39–55. 10.1089/dna.2023.0288. 38079253 10.1089/dna.2023.0288 PMC10825292
45. Feng Y Zhang L Wu J Khadka B Fang Z Gu J Tang B Xiao R Pan G Liu J Circrna circ_0000190 inhibits the progression of multiple myeloma through modulating mir-767-5p/mapk4 pathway J Exp Clin Cancer Res 2019 38 1 54 10.1186/s13046-019-1071-9 30728056 PMC6364482 Feng Y, Zhang L, Wu J, Khadka B, Fang Z, Gu J, Tang B, Xiao R, Pan G, Liu J. Circrna circ_0000190 inhibits the progression of multiple myeloma through modulating mir-767-5p/mapk4 pathway. J Exp Clin Cancer Res. 2019;38(1):54. 10.1186/s13046-019-1071-9. 30728056 10.1186/s13046-019-1071-9 PMC6364482
46. Wang P Zhang Y Lin Q Zhou J Lv X Song Y Hsa_circ_0111738 inhibits tumor progression and angiogenesis in multiple myeloma by sponging mir-1233-3p to regulate hif-1 signaling pathway Arch Med Res 2023 54 4 299 309 10.1016/j.arcmed.2023.05.002 37211508 Wang P, Zhang Y, Lin Q, Zhou J, Lv X, Song Y. Hsa_circ_0111738 inhibits tumor progression and angiogenesis in multiple myeloma by sponging mir-1233-3p to regulate hif-1 signaling pathway. Arch Med Res. 2023;54(4):299–309. 10.1016/j.arcmed.2023.05.002. 37211508 10.1016/j.arcmed.2023.05.002
47. Min J Mao J Shi H Peng Y Xu X Guo M Tang X Yang Y Gu C Cul4a-ddb1-circrfwd2 e3 ligase complex mediates the ubiquitination of p27 to promote multiple myeloma proliferation Exp Hematol Oncol 2024 13 1 116 10.1186/s40164-024-00582-8 39578820 PMC11583565 Min J, Mao J, Shi H, Peng Y, Xu X, Guo M, Tang X, Yang Y, Gu C. Cul4a-ddb1-circrfwd2 e3 ligase complex mediates the ubiquitination of p27 to promote multiple myeloma proliferation. Exp Hematol Oncol. 2024;13(1):116. 10.1186/s40164-024-00582-8. 39578820 10.1186/s40164-024-00582-8 PMC11583565
48. Papatsirou M Kontos CK Ntanasis-Stathopoulos I Malandrakis P Sideris DC Fotiou D Liacos CI Gavriatopoulou M Kastritis E Dimopoulos MA Scorilas A Terpos E Exploring the molecular biomarker utility of circcct3 in multiple myeloma: a favorable prognostic indicator, particularly for r-iss ii patients Hemasphere 2024 8 1 e34 10.1002/hem3.34 38434522 PMC10878196 Papatsirou M, Kontos CK, Ntanasis-Stathopoulos I, Malandrakis P, Sideris DC, Fotiou D, Liacos CI, Gavriatopoulou M, Kastritis E, Dimopoulos MA, Scorilas A, Terpos E. Exploring the molecular biomarker utility of circcct3 in multiple myeloma: a favorable prognostic indicator, particularly for r-iss ii patients. Hemasphere. 2024;8(1):e34. 10.1002/hem3.34. 38434522 10.1002/hem3.34 PMC10878196
49. Gao J Qu J Xiao B Huang Q Zhu C Dai Z Wu K Li L Zeng T The diagnostic value of serum lncrna catg00000112921.1 as a marker of multiple myeloma Curr Probl Cancer 2024 10.1016/j.currproblcancer.2023.101057 38070464 Gao J, Qu J, Xiao B, Huang Q, Zhu C, Dai Z, Wu K, Li L, Zeng T. The diagnostic value of serum lncrna catg00000112921.1 as a marker of multiple myeloma. Curr Probl Cancer. 2024. 10.1016/j.currproblcancer.2023.101057. 38070464 10.1016/j.currproblcancer.2023.101057
50. Long X Wen F Li J Huang X Lncrna fezf1-as1 accelerates multiple myeloma progression by regulating igf2bp1/bzw2 signaling Hematol Oncol 2023 41 4 694 703 10.1002/hon.3157 37125488 Long X, Wen F, Li J, Huang X. Lncrna fezf1-as1 accelerates multiple myeloma progression by regulating igf2bp1/bzw2 signaling. Hematol Oncol. 2023;41(4):694–703. 10.1002/hon.3157. 37125488 10.1002/hon.3157
51. Wang CS Zhang XB Zhu XT Chen RS Nbr2/mir-561-5p/dlc1 axis inhibited the development of multiple myeloma by activating the ampk/mtor pathway to repress glycolysis Neoplasma 2022 69 5 1165 1174 10.4149/neo_2022_211102N1559 35951458 Wang CS, Zhang XB, Zhu XT, Chen RS. Nbr2/mir-561-5p/dlc1 axis inhibited the development of multiple myeloma by activating the ampk/mtor pathway to repress glycolysis. Neoplasma. 2022;69(5):1165–74. 10.4149/neo_2022_211102N1559. 35951458 10.4149/neo_2022_211102N1559
52. Ma T Chen Y Yi ZG Liu J Li YH Bai J Tie WT Huang M Zhu XF Wang J Du J Zuo XQ Li Q Lin FL Tang L Guo J Xiao HW Lei Q Ma XL Li LJ Zhang LS Norad promotes multiple myeloma cell progression via bmp6/p-erk1/2 axis Cell Signal 2022 100 110474 10.1016/j.cellsig.2022.110474 36126794 Ma T, Chen Y, Yi ZG, Liu J, Li YH, Bai J, Tie WT, Huang M, Zhu XF, Wang J, Du J, Zuo XQ, Li Q, Lin FL, Tang L, Guo J, Xiao HW, Lei Q, Ma XL, Li LJ, Zhang LS. Norad promotes multiple myeloma cell progression via bmp6/p-erk1/2 axis. Cell Signal. 2022;100:110474. 10.1016/j.cellsig.2022.110474. 36126794 10.1016/j.cellsig.2022.110474
53. Xu Y Wang T Wan J Ma D Zhang H Cheng D Yang J Wang M Long non-coding rna neat1 promotes multiple myeloma malignant transformation via targeting mir-485-5p/abcb8 Hematology 2024 29 1 2422153 10.1080/16078454.2024.2422153 39475764 Xu Y, Wang T, Wan J, Ma D, Zhang H, Cheng D, Yang J, Wang M. Long non-coding rna neat1 promotes multiple myeloma malignant transformation via targeting mir-485-5p/abcb8. Hematology. 2024;29(1):2422153. 10.1080/16078454.2024.2422153. 39475764 10.1080/16078454.2024.2422153
54. Yan H Gao S Xu A Zuo L Zhang J Zhao Y Cheng Q Yin X Sun C Hu Y Malat1 regulates network of microrna-15a/16-vegfa to promote tumorigenesis and angiogenesis in multiple myeloma Carcinogenesis 2023 44 10–11 760 772 10.1093/carcin/bgad053 37549238 Yan H, Gao S, Xu A, Zuo L, Zhang J, Zhao Y, Cheng Q, Yin X, Sun C, Hu Y. Malat1 regulates network of microrna-15a/16-vegfa to promote tumorigenesis and angiogenesis in multiple myeloma. Carcinogenesis. 2023;44(10–11):760–72. 10.1093/carcin/bgad053. 37549238 10.1093/carcin/bgad053
55. Wang QM Lian GY Sheng SM Xu J Ye LL Min C Guo SF Exosomal lncrna neat1 inhibits nk-cell activity to promote multiple myeloma cell immune escape via an ezh2/pbx1 axis Mol Cancer Res 2024 22 2 125 136 10.1158/1541-7786.MCR-23-0282 37889101 Wang QM, Lian GY, Sheng SM, Xu J, Ye LL, Min C, Guo SF. Exosomal lncrna neat1 inhibits nk-cell activity to promote multiple myeloma cell immune escape via an ezh2/pbx1 axis. Mol Cancer Res. 2024;22(2):125–36. 10.1158/1541-7786.MCR-23-0282. 37889101 10.1158/1541-7786.MCR-23-0282
56. Song Y Guo N Zi F Zheng J Cheng J Lncrna h19 plays a role in multiple myeloma via interacting with hnrnpa2b1 to stabilize bet proteins by targeting osteoclasts and osteoblasts Int Immunopharmacol 2024 142 Pt B 113080 10.1016/j.intimp.2024.113080 39288624 Song Y, Guo N, Zi F, Zheng J, Cheng J. Lncrna h19 plays a role in multiple myeloma via interacting with hnrnpa2b1 to stabilize bet proteins by targeting osteoclasts and osteoblasts. Int Immunopharmacol. 2024;142(Pt B):113080. 10.1016/j.intimp.2024.113080. 39288624 10.1016/j.intimp.2024.113080
57. Ning J Yang R Wang H Ma H Cui L Lncrna malat1 silencing represses cxcl12-induced proliferation, invasion, and homing behavior in multiple myeloma by inhibiting cxcr4 Hematology 2024 29 1 2422154 10.1080/16078454.2024.2422154 39503766 Ning J, Yang R, Wang H, Ma H, Cui L. Lncrna malat1 silencing represses cxcl12-induced proliferation, invasion, and homing behavior in multiple myeloma by inhibiting cxcr4. Hematology. 2024;29(1):2422154. 10.1080/16078454.2024.2422154. 39503766 10.1080/16078454.2024.2422154
58. Zhou M Deng T Tan Y Liu L Wang M Mir-26 inhibits proliferation and promotes apoptosis of multiple myeloma cells by targeting bnip3 Cell Mol Biol (Noisy-le-grand) 2023 69 11 260 265 10.14715/cmb/2023.69.11.39 38054975 Zhou M, Deng T, Tan Y, Liu L, Wang M. Mir-26 inhibits proliferation and promotes apoptosis of multiple myeloma cells by targeting bnip3. Cell Mol Biol (Noisy-le-grand). 2023;69(11):260–5. 10.14715/cmb/2023.69.11.39. 38054975 10.14715/cmb/2023.69.11.39
59. Liu X Qin L Li W Fei F Microrna-1179 targets epiregulin (ereg) regulates the proliferation and metastasis of human multiple myeloma cells Acta Biochim Pol 2023 70 2 389 393 10.18388/abp.2020_6644 37329522 Liu X, Qin L, Li W, Fei F. Microrna-1179 targets epiregulin (ereg) regulates the proliferation and metastasis of human multiple myeloma cells. Acta Biochim Pol. 2023;70(2):389–93. 10.18388/abp.2020_6644. 37329522 10.18388/abp.2020_6644
60. Long S Long S He H Luo L Liu M Ding T Exosomal mir-182 derived from bone marrow mesenchymal stem cells drives carfilzomib resistance of multiple myeloma cells by targeting sox6 J Orthop Surg Res 2023 18 1 937 10.1186/s13018-023-04399-9 38062424 PMC10702080 Long S, Long S, He H, Luo L, Liu M, Ding T. Exosomal mir-182 derived from bone marrow mesenchymal stem cells drives carfilzomib resistance of multiple myeloma cells by targeting sox6. J Orthop Surg Res. 2023;18(1):937. 10.1186/s13018-023-04399-9. 38062424 10.1186/s13018-023-04399-9 PMC10702080
61. Zhang H Du Z Tu C Zhou X Menu E Wang J Hypoxic bone marrow stromal cells secrete mir-140-5p and mir-28-3p that target spred1 to confer drug resistance in multiple myeloma Cancer Res 2024 84 1 39 55 10.1158/0008-5472.CAN-23-0189 37756570 Zhang H, Du Z, Tu C, Zhou X, Menu E, Wang J. Hypoxic bone marrow stromal cells secrete mir-140-5p and mir-28-3p that target spred1 to confer drug resistance in multiple myeloma. Cancer Res. 2024;84(1):39–55. 10.1158/0008-5472.CAN-23-0189. 37756570 10.1158/0008-5472.CAN-23-0189
62. Zhang R Zhang D Luo Y Sun Y Duan C Yang J Wei J Li X Lu Y Lai X Mir-34a promotes the immunosuppressive function of multiple myeloma-associated macrophages by dampening the tlr-9 signaling Cancer Med 2024 13 11 e7387 10.1002/cam4.7387 38864479 PMC11167606 Zhang R, Zhang D, Luo Y, Sun Y, Duan C, Yang J, Wei J, Li X, Lu Y, Lai X. Mir-34a promotes the immunosuppressive function of multiple myeloma-associated macrophages by dampening the tlr-9 signaling. Cancer Med. 2024;13(11):e7387. 10.1002/cam4.7387. 38864479 10.1002/cam4.7387 PMC11167606
63. Mikulski D Nowicki M Drozdz I Misiewicz M Koscielny KP Okonski K Krawiec K Perdas E Wierzbowska A Fendler W High serum mir-223-3p expression level predicts complete response and prolonged overall survival in multiple myeloma patients undergoing autologous hematopoietic stem cell transplantation Front Oncol 2023 13 1250355 10.3389/fonc.2023.1250355 37829335 PMC10565214 Mikulski D, Nowicki M, Drozdz I, Misiewicz M, Koscielny KP, Okonski K, Krawiec K, Perdas E, Wierzbowska A, Fendler W. High serum mir-223-3p expression level predicts complete response and prolonged overall survival in multiple myeloma patients undergoing autologous hematopoietic stem cell transplantation. Front Oncol. 2023;13:1250355. 10.3389/fonc.2023.1250355. 37829335 10.3389/fonc.2023.1250355 PMC10565214
64. Gkioka AI Tsota M Koudouna A Gkiokas A Mitropoulou CA Palaiokrassa A Alexandropoulos A Papadatou-Gigante M Bartzi V Tryfou TM Sfikakis PP Dedoussis GV Kyrtsonis MC Circulating mir-16 and mir-21 levels in multiple myeloma: prognostic significance of survival and response to lenalidomide treatment Int J Mol Sci 2024 10.3390/ijms25116065 38892251 PMC11172882 Gkioka AI, Tsota M, Koudouna A, Gkiokas A, Mitropoulou CA, Palaiokrassa A, Alexandropoulos A, Papadatou-Gigante M, Bartzi V, Tryfou TM, Sfikakis PP, Dedoussis GV, Kyrtsonis MC. Circulating mir-16 and mir-21 levels in multiple myeloma: prognostic significance of survival and response to lenalidomide treatment. Int J Mol Sci. 2024. 10.3390/ijms25116065. 38892251 10.3390/ijms25116065 PMC11172882
65. Song M Yao H Sun Z Chen D Xu X Long G Wu L Hu W Mettl3/ythdc1-medicated m6a modification of circrna3634 regulates the proliferation and differentiation of antler chondrocytes by mir-124486-5-mapk1 axis Cell Mol Biol Lett 2023 28 1 101 10.1186/s11658-023-00515-z 38062349 PMC10702069 Song M, Yao H, Sun Z, Chen D, Xu X, Long G, Wu L, Hu W. Mettl3/ythdc1-medicated m6a modification of circrna3634 regulates the proliferation and differentiation of antler chondrocytes by mir-124486-5-mapk1 axis. Cell Mol Biol Lett. 2023;28(1):101. 10.1186/s11658-023-00515-z. 38062349 10.1186/s11658-023-00515-z PMC10702069
66. Zhou J Yao L Su Y Tian L Igf2bp3 loss inhibits cell progression by upregulating has_circrna_103820, and hsa_circrna_103820-encoded peptide inhibits cell progression by inactivating the akt pathway in lung cancer Chem Biol Drug Des 2024 103 2 e14473 10.1111/cbdd.14473 38378275 Zhou J, Yao L, Su Y, Tian L. Igf2bp3 loss inhibits cell progression by upregulating has_circrna_103820, and hsa_circrna_103820-encoded peptide inhibits cell progression by inactivating the akt pathway in lung cancer. Chem Biol Drug Des. 2024;103(2):e14473. 10.1111/cbdd.14473. 38378275 10.1111/cbdd.14473
67. Zhong X Peng Y Zhang X Peng L Ma K Huang Y Yang X M6a-modified circ_0124554 promotes colorectal cancer progression and radioresistance through the mir-1184/lasp1 pathway Pathol Res Pract 2024 253 154950 10.1016/j.prp.2023.154950 38091882 Zhong X, Peng Y, Zhang X, Peng L, Ma K, Huang Y, Yang X. M6a-modified circ_0124554 promotes colorectal cancer progression and radioresistance through the mir-1184/lasp1 pathway. Pathol Res Pract. 2024;253:154950. 10.1016/j.prp.2023.154950. 38091882 10.1016/j.prp.2023.154950
68. Chen K Zhang J Meng L Kong L Lu M Wang Z Wang W The epigenetic downregulation of lncghrlos mediated by rna m6a methylase zcchc4 promotes colorectal cancer tumorigenesis J Exp Clin Cancer Res 2024 43 1 44 10.1186/s13046-024-02965-5 38326863 PMC10848513 Chen K, Zhang J, Meng L, Kong L, Lu M, Wang Z, Wang W. The epigenetic downregulation of lncghrlos mediated by rna m6a methylase zcchc4 promotes colorectal cancer tumorigenesis. J Exp Clin Cancer Res. 2024;43(1):44. 10.1186/s13046-024-02965-5. 38326863 10.1186/s13046-024-02965-5 PMC10848513
69. Ji X Wan X Sun H Deng Q Meng S Xie B Zhou S Mettl14 enhances the m6a modification level of lncrna mstrg.292666.16 to promote the progression of non-small cell lung cancer Cancer Cell Int 2024 24 1 61 10.1186/s12935-024-03250-3 38326804 PMC10851476 Ji X, Wan X, Sun H, Deng Q, Meng S, Xie B, Zhou S. Mettl14 enhances the m6a modification level of lncrna mstrg.292666.16 to promote the progression of non-small cell lung cancer. Cancer Cell Int. 2024;24(1):61. 10.1186/s12935-024-03250-3. 38326804 10.1186/s12935-024-03250-3 PMC10851476
70. Yang Z Luo Y Zhang F Ma L Exosome-derived lncrna a1bg-as1 attenuates the progression of prostate cancer depending on zc3h13-mediated m6a modification Cell Div 2024 19 1 5 10.1186/s13008-024-00110-4 38351022 PMC10863231 Yang Z, Luo Y, Zhang F, Ma L. Exosome-derived lncrna a1bg-as1 attenuates the progression of prostate cancer depending on zc3h13-mediated m6a modification. Cell Div. 2024;19(1):5. 10.1186/s13008-024-00110-4. 38351022 10.1186/s13008-024-00110-4 PMC10863231
71. Zhou X Chang L Liang Q Zhao R Xiao Y Xu Z Yu L The m6a methyltransferase mettl3 drives thyroid cancer progression and lymph node metastasis by targeting linc00894 Cancer Cell Int 2024 24 1 47 10.1186/s12935-024-03240-5 38291427 PMC10826051 Zhou X, Chang L, Liang Q, Zhao R, Xiao Y, Xu Z, Yu L. The m6a methyltransferase mettl3 drives thyroid cancer progression and lymph node metastasis by targeting linc00894. Cancer Cell Int. 2024;24(1):47. 10.1186/s12935-024-03240-5. 38291427 10.1186/s12935-024-03240-5 PMC10826051
72. Zhang S Zhao BS Zhou A Lin K Zheng S Lu Z Chen Y Sulman EP Xie K Bogler O Majumder S He C Huang S M(6)a demethylase alkbh5 maintains tumorigenicity of glioblastoma stem-like cells by sustaining foxm1 expression and cell proliferation program Cancer Cell 2017 31 4 591 606 10.1016/j.ccell.2017.02.013 28344040 PMC5427719 Zhang S, Zhao BS, Zhou A, Lin K, Zheng S, Lu Z, Chen Y, Sulman EP, Xie K, Bogler O, Majumder S, He C, Huang S. M(6)a demethylase alkbh5 maintains tumorigenicity of glioblastoma stem-like cells by sustaining foxm1 expression and cell proliferation program. Cancer Cell. 2017;31(4):591–606. 10.1016/j.ccell.2017.02.013. 28344040 10.1016/j.ccell.2017.02.013 PMC5427719
73. Liang L Liu S Wu Q Chen R Jiang S Yang Z M6a-mediated upregulation of mirna-193a aggravates cardiomyocyte apoptosis and inflammatory response in sepsis-induced cardiomyopathy via the mettl3/ mirna-193a/bcl2l2 pathway Exp Cell Res 2023 430 1 113712 10.1016/j.yexcr.2023.113712 37414203 Liang L, Liu S, Wu Q, Chen R, Jiang S, Yang Z. M6a-mediated upregulation of mirna-193a aggravates cardiomyocyte apoptosis and inflammatory response in sepsis-induced cardiomyopathy via the mettl3/ mirna-193a/bcl2l2 pathway. Exp Cell Res. 2023;430(1):113712. 10.1016/j.yexcr.2023.113712. 37414203 10.1016/j.yexcr.2023.113712
74. Li S Du M Xu K Ben S Zhu T Guo M Xin J Zhu L Gu D Zhang Z Wang M Genetic modulation of bet1l confers colorectal cancer susceptibility by reducing mirna binding and m6a modification Cancer Res 2023 83 13 2142 2154 10.1158/0008-5472.CAN-22-0065 37115853 Li S, Du M, Xu K, Ben S, Zhu T, Guo M, Xin J, Zhu L, Gu D, Zhang Z, Wang M. Genetic modulation of bet1l confers colorectal cancer susceptibility by reducing mirna binding and m6a modification. Cancer Res. 2023;83(13):2142–54. 10.1158/0008-5472.CAN-22-0065. 37115853 10.1158/0008-5472.CAN-22-0065
75. Gong Y Jiang Q Liu L Liao Q Yu J Xiang Z Luo X Mettl3-mediated m6a modification promotes processing and maturation of pri-mirna-19a to facilitate nasopharyngeal carcinoma cell proliferation and invasion Physiol Genomics 2022 54 9 337 349 10.1152/physiolgenomics.00007.2022 35759451 Gong Y, Jiang Q, Liu L, Liao Q, Yu J, Xiang Z, Luo X. Mettl3-mediated m6a modification promotes processing and maturation of pri-mirna-19a to facilitate nasopharyngeal carcinoma cell proliferation and invasion. Physiol Genomics. 2022;54(9):337–49. 10.1152/physiolgenomics.00007.2022. 35759451 10.1152/physiolgenomics.00007.2022
76. Liang H Fang C Zhang L Methyltransferase-like 3 facilitates the stem cell properties of esophageal cancer by upregulating patched homolog 1 via n6-methyladenosine methylation Am J Physiol Cell Physiol 2023 325 3 C770 C779 10.1152/ajpcell.00136.2023 37575058 Liang H, Fang C, Zhang L. Methyltransferase-like 3 facilitates the stem cell properties of esophageal cancer by upregulating patched homolog 1 via n6-methyladenosine methylation. Am J Physiol Cell Physiol. 2023;325(3):C770–9. 10.1152/ajpcell.00136.2023. 37575058 10.1152/ajpcell.00136.2023
77. Guo N Song Y Zi F Zheng J Cheng J Abnormal expression pattern of lncrna h19 participates in multiple myeloma bone disease by unbalancing osteogenesis and osteolysis Int Immunopharmacol 2023 119 110058 10.1016/j.intimp.2023.110058 37058751 Guo N, Song Y, Zi F, Zheng J, Cheng J. Abnormal expression pattern of lncrna h19 participates in multiple myeloma bone disease by unbalancing osteogenesis and osteolysis. Int Immunopharmacol. 2023;119:110058. 10.1016/j.intimp.2023.110058. 37058751 10.1016/j.intimp.2023.110058
78. Chen S Duan X He Y Chen W 2024 Mettl3 promotes osteogenic differentiation of human umbilical cord mesenchymal stem cells by upregulating m6a modification of circcttn Biosci Rep 10.1042/BSR20231186 PMC10932744 38358895 Chen S, Duan X, He Y, Chen W. Mettl3 promotes osteogenic differentiation of human umbilical cord mesenchymal stem cells by upregulating m6a modification of circcttn. 2024. Biosci Rep. 10.1042/BSR20231186. 10.1042/BSR20231186 PMC10932744 38358895
79. Yang H Wang W Liu H Zhang C Cao Y Long L Han X Wang Y Yan F Li G Zhu M Jin L Fan Z Mir615–3p inhibited fbln1 and osteogenic differentiation of umbilical cord mesenchymal stem cells by associated with ythdf2 in a m(6) a-mirna interaction manner Cell Prolif 2024 10.1111/cpr.13607 38353178 PMC11150146 Yang H, Wang W, Liu H, Zhang C, Cao Y, Long L, Han X, Wang Y, Yan F, Li G, Zhu M, Jin L, Fan Z. Mir615–3p inhibited fbln1 and osteogenic differentiation of umbilical cord mesenchymal stem cells by associated with ythdf2 in a m(6) a-mirna interaction manner. Cell Prolif. 2024. 10.1111/cpr.13607. 38353178 10.1111/cpr.13607 PMC11150146
80. Liu R Zhong Y Chen R Chu C Liu G Zhou Y Huang Y Fang Z Liu H M(6)a reader hnrnpa2b1 drives multiple myeloma osteolytic bone disease Theranostics 2022 12 18 7760 7774 10.7150/thno.76852 36451863 PMC9706590 Liu R, Zhong Y, Chen R, Chu C, Liu G, Zhou Y, Huang Y, Fang Z, Liu H. M(6)a reader hnrnpa2b1 drives multiple myeloma osteolytic bone disease. Theranostics. 2022;12(18):7760–74. 10.7150/thno.76852. 36451863 10.7150/thno.76852 PMC9706590
81. Yao L Li T Teng Y Guo J Zhang H Xia L Wu Q Alkhb5-demethylated lncrna snhg15 promotes myeloma tumorigenicity by increasing chromatin accessibility and recruiting h3k36me3 modifier setd2 Am J Physiol Cell Physiol 2024 326 3 C684 C697 10.1152/ajpcell.00348.2023 38145297 PMC11193452 Yao L, Li T, Teng Y, Guo J, Zhang H, Xia L, Wu Q. Alkhb5-demethylated lncrna snhg15 promotes myeloma tumorigenicity by increasing chromatin accessibility and recruiting h3k36me3 modifier setd2. Am J Physiol Cell Physiol. 2024;326(3):C684–97. 10.1152/ajpcell.00348.2023. 38145297 10.1152/ajpcell.00348.2023 PMC11193452