Role of microRNAs in hematological malignancies research: A bibliometric analysis.

1. Introduction

MicroRNAs (miRNAs) are important for gene expression regulation and their alterations have been found more frequently in the development and evolution of a variety of plasma disorders, including leukemias, lymphomas, and myelodysplastic syndromes. [ 1 – 3 ] miRNAs are short, non-coding RNA molecules with length of which is: 18 to 25 nucleotides and that bind to complementary sequences located in the 3′ untranslated region of target mRNA transcripts, resulting in either degradation of the mRNA molecule or inhibition of translation of the mRNA into protein. This regulatory mechanism is important for the control of normal hematopoiesis, and disturbances in miRNA expression contribute to hematopoietic imbalance, promoting the development of blood malignancies as well as a number of other hematological diseases. [ 4 – 6 ]

During normal hematopoiesis, miRNAs play a role in the differentiation, proliferation, and apoptosis of hematopoietic stem cells and their offspring. Certain miRNAs are required for distinct time associations of cell development. [ 7 – 9 ] For example, miR-223 has been associated with the differentiation of myeloid cells, including granulocyte development, while miR-150 has lymphoid lineage biasing potential over the myeloid lineage and thus affects the development of B cells and T cells. Similarly, miR-181a has been described to be involved in the development of T and B cells, especially during the immune response. In the context of blood diseases, alterations in these miRNAs may alter the putative pathways leading to uncontrolled proliferation, abnormal differentiation, or inability to undergo apoptosis of hematopoietic cells. [ 4 – 6 ]

Different types of diseases are caused by altered miRNAs, and on its part, acute myeloid leukemia (AML), for instance, does not seem to be an exception as loss of members of the mir-29 family (mp-29a, miR-29b, and miR-29c) is a normal phenomenon, which in turn causes oncogenic target genes such as DNMT3A and MCL1 to be expressed, thus promoting cell survival and proliferative activities. [ 10 – 12 ] MiR-15a and miR-16-1, on their part, appear to greatly benefit from losses in chromosome 13q deletions especially in chronic-lymphocytic leukaemia (CLL). It also results in increased expression B-cell lymphoma 2 (BCL2) which prevents normal death in CLL cells. In addition, in acute lymphoblastic-leukemia, miR-125b has also been found to be highly expressed, leading to the proliferation of B-cell precursors. [ 4 , 9 , 13 ]

Lymphomas also show miRNA signature dysregulation patterns. In diffuse large B-cell lymphoma (DLBCL), there is frequent overexpression miR-155 which is related to poor outcomes. [ 14 ] This miRNA promotes cellular growth by inhibiting SHIP1, which is a negative modulator of the phosphoinositide 3-kinase/protein kinase B signaling pathway. The decrease in miR-101 in follicular lymphoma is associated with the increased expression of Enhancer of Zeste Homolog-2, which is a key player in chromatin remodeling and aids in the proliferation and survival of cancer cells. Likewise, in myelodysplastic syndromes, miR-145, and particularly miR-146a, are frequently downregulated, especially in patients with 5q deletions. These miRNAs target genes associated with erythropoiesis and megakaryopoiesis, and their absence results in the apoptosis of hematopoietic progenitor cells, which increases the chances of developing leukemia. [ 4 ]

Dysregulation of miRNAs in hematological cancers may result from various causes. Loss-of-function mutations in miRNA genes, such as deletions, aberrations, and mutations, can be deleterious. For example, CLL has chromosomal loss involving miR-15a and mir-16-1 which leads to BCL2 overexpression. [ 3 ] Hypermethylation of regions flanking the promoters of miRNA genes suppresses the expression of tumor-suppressor miRNAs, while histone modification also alters the expression of miRNAs. [ 12 ] Furthermore, there are growth-promoting miRNAs that, when expressed, are probably responsible for increased cell metabolism and growth due to the presence of oncogenic transcription factors such as myelocytomatosis oncogene. Other transcription factors may also suppress the expression of critical miRNAs required for tumor growth. [ 4 ]

In hematological malignancies, there is growing optimism over the use of miRNAs as biological markers, given how their expression changes over the various stages of the disease, the subtypes of the disease, and prognosis. For example, bleeding miR-155, which is the predominant miRNA in DLBCL, could potentially help steer treatment methods due to its correlation with poor outcome. Plasmas in the blood circulation containing miR items such as miR-16 and miR have been suggested for leukemia diagnosis and monitoring work for noninvasive spotting techniques. [ 15 – 19 ]

Bibliometric analysis is an effective method for assessing scholarly citation impact or intellectual architecture in certain academic areas. By exploring citation analysis, co-authorship patterns, and word usage, it explains development, changes, and important publications. [ 20 , 21 ] In rapidly developing areas, such as miRNA studies of hematological disorders, bibliometric methods provide information on fruitful researchers, notable organizations, and prominent journals, tracing the progress of critical issues and topical areas. This method provides a clear conception of useful primary studies, lists the most cited articles, and even exposes cross-border studies that can determine subsequent studies and financing areas. A bibliometric study on the role of miRNAs in hematological disorders will provide a better history of the development of this field, assist in outlining areas for further exploration, and promote the use of miRNA-based diagnostics and therapies in clinical practice.

2. Methods

2.1. Database selection

Data relevant to this study were obtained from Scopus, which is suited for its comprehensive coverage of biomedical research and great indexing standards. Scopus was compiled, as it included a large university of reputable journals with high indexing disciplines that could provide help in trend mapping and the study of important contributions. [ 22 ]

2.2. Data retrieval

Searches were undertaken on Scopus using following formula: [TITLE-ABS-KEY((“microRNA” OR “miRNA”) AND (“hematological disorders” OR “hematologic neoplasms” OR “acute myeloid leukemia” OR “chronic lymphocytic leukemia” OR “Hodgkin lymphoma” OR “Non-Hodgkin lymphoma” OR “multiple myeloma” OR “hemophilia” OR “myelodysplastic syndromes” OR “thrombocytopenia”))] concentrating on active research focused on miRNAs in blood and other related cancers. The initial search resulted in 5348 documents. The inclusion criteria were defined as original research articles written in the English language, while excluding other types of documents, including conference abstracts, work of editors, or chapters of books to ensure accuracy and reliability. The selected timeframe of the search was open, and potential articles from Scopus were evaluated chronologically, as well as looking at recent works in this area. The data were gathered in language, which included translations, and were in formats conducive to the analysis software. This enabled us to carry out an elaborate analysis of publications and their metadata, citation information, and established networks and themes. The final data (N = 2899) were exported in CVS and BibTex formats. The data were extracted from the September 1, 2024.

2.3. Data analysis

Analysis of the bibliometric data was performed using VOSviewer [ 23 ] and Biblioshiny, [ 24 ] 2 programs designed to visualize and analyze bibliometric indicators. Using VOSviewer, they prepared illustrations of citation networks, co-authorship relationships, and maps of keyword co-occurrence, making it possible to determine the most active authors, institutions, and networks. The use of VOSviewer clustering algorithms also facilitated the localization of keyword groups to determine the major and hot areas of miRNA research in hematology. At another extreme, a web interface for the R package Biblioshiny, provided additional analytical tools for the assessment of the publication trends, country output, and impact ratio of various journals. This tool provided advanced bibliometric indicators, the most productive journals, and detailed patterns of changes in the development of the study area. [ 23 , 24 ]

To understand the density and centrality of various thematic domains associated with the research of miRNAs in hematological disorders, thematic mapping analysis was also performed, as a measure of inter-theme development and cohesion with the area, whereas centrality measurement indicates the strength of link among the themes and other research domains and adjectives’ relevance and impact for the relevant research. Centrality and density are altered composition themes or major themes that influence a well-established field of research, while high centrality but low density values are considered basic. High centrality and low density of the items do not indicate a definite area of focus but narrow advanced areas termed as throttle. [ 21 , 25 ] This analysis played an important role in revealing the structure and interconnectedness of the research topics, with the possibility of determining mature, core, and growing ones in the sphere of miRNAs within the context of hematological pathology. Bradford law was used to identify the core journals. [ 24 ]

3. Results

3.1. Inception, growth, and recognition

Since its inception in 2003 with a single publication, research on miRNAs in hematological malignancies has shown a robust upward trajectory, marked by an annual growth rate of 27.41%. The highest number of documents was recorded in 2021, with 318 publications (Fig. 1 ). Over the past 5 years (2019–2023), the field has consistently produced a significant volume of research, ranging from 238 documents in 2019 to 200 in 2023, reflecting a strong, albeit slightly fluctuating, research interest. Similarly, in the last 10 years (2014–2023), the number of documents increased from 128 to 200, further demonstrating a substantial growth trend. The relatively young document average age of 6.13 years underscores the balance between historical contributions and new advancements in this dynamic research domain. Collectively, these metrics indicate that the field is experiencing sustained growth and scholarly engagement.

There is an average of 42.4 total citations per document, which indicates the relevance of the research outputs in this area of study. In Figure 1 , the changes over time in the mean total number of citations per article per year are depicted, shedding light on the changing impact of miRNA research on hematological malignancies. For instance, several papers, such as 2004 2103 and 2005 1672.17, were able to achieve a high basket of 672.17, which were critical papers that later made it possible for subsequent investigations. Since the initial years, there has been a consistent fall in the mean citations per article due to the saturation of newer papers that are yet to reach their citation potential. However, there is a steady amount of scholarly output and citation activity, which shows the importance and visibility of work in the area of study.

3.2. Global landscape, visualization of co-authorship, and impactful countries

Research on miRNAs in hematological malignancies spans 73 countries, representing 37.6% of global participation. China had 31.54%, followed by the USA (21.71%) and Italy (9.47%). Other key contributors included Germany, Spain, and Iran. Activity is concentrated in Asia, North America, and Europe, with notable, albeit smaller, contributions from South America, Africa, and the Middle East. Figure 2 A shows the global distribution, with denser blue colors indicating higher productivity, highlighting the leading countries as hubs for research and collaboration. The international co-authorship rate for research on miRNAs in hematological malignancies was 23.96%, highlighting notable global collaboration. The total link strength (TLS) generated using VOSviewer measures collaboration intensity among countries. Leading in the United States (640), followed by Italy (333), Germany (267), and China (225). Other prominent collaborators included the United Kingdom (154), France (120), the Netherlands (119), Canada (109), and Spain (108). Figure 2 B depicts these collaborations, where the nodes represent countries with larger node sizes, indicating stronger collaborative ties. Figure 2 C shows the ratio of single-country publications (SCP) and multiple-country publications (MCP) for major contributing countries in research on miRNAs in hematological malignancies. China has a high SCP ratio (0.90) and low MCP ratio (0.10), indicating the predominance of domestically focused research. In contrast, Canada demonstrates a high MCP ratio (0.64) and a lower SCP (0.36), highlighting stronger international collaboration. The USA, Italy, Germany, and other countries exhibit varying degrees of collaboration with notable international participation, as represented by their MCP and SCP ratios. Figure 2 C shows these distributions. Based on the overlay visualization in VOSviewer (Fig. 2 D), Egypt, India, Iran, Turkey, Iraq, and Russia were highlighted as countries that have recently entered into research cooperation with others. The yellow color indicates their recent engagement in collaborative efforts within the research field of miRNAs in hematological malignancies, suggesting emerging and growing interest and partnerships in this domain.

The most productive affiliations in the research field of miRNAs in hematological malignancies were led by Ohio State University, USA, with 201 articles. Huazhong University of Science and Technology, China, followed by 87 articles, and Harvard Medical School, USA, had 85 articles. Other notable contributors include Ohio State University (62 articles, USA), The University of Texas MD Anderson Cancer Center (55 articles, USA), the University of Ferrara (54 articles, Italy), Central South University (52 articles, China), and the University of Chicago (45 articles, USA). Additional affiliations included the University of Texas MD Anderson Cancer Center (45 articles, USA) and Affiliated Hospital of Nantong University (43 articles, China).

3.3. Prominent scholars

Table 1 highlights prominent scholars in the research field of miRNAs in hematological malignancies, ranked by key bibliometric indicators. Dr Croce, C.M., has led with an h -index of 45, a g -index of 67, and a total citation count of 24,682 across 67 publications since 2004, reflecting his influential contributions and high citation impact. Marcucci, G. follows with an h -index of 41, 8001 citations, and 58 publications since 2006. Bloomfield, C.D., with an h -index of 35 and 7032 citations from 43 publications, has been active since 2008. Other notable scholars include Tassone, P. ( h -index 35, 3305 citations, 46 publications since 2012) and Caligiuri, M.A. ( h -index 31, 5161 citations, 36 publications since 2008). Calin, G.A., despite a relatively lower h -index of 29, has had a high citation count of 18,874 over 42 publications since 2004, highlighting the significant influence of his work. Additional prominent researchers are Garzon, R., Li, Y., and Neri, A., each with h -indices of 29 and notable contributions in terms of citations and publication counts, demonstrating their impact on advancing this field.

3.4. Relevant sources

The core journals in the research field of miRNAs in hematological malignancies, as shown in Figure 3 , are predominantly represented in Zone 1. Leading the list is The journal Blood, with a frequency of 112 publications, followed by Oncotarget (84 publications) and Leukemia (73 publications). Other key journals included PLOS ONE (67 publications), Oncology Letters (59 publications), and Leukemia Research (53 publications). The cumulative frequency of Zone 1 journals extends up to Cells with 22 publications, underscoring their significance as central sources of scholarly output in this domain. The transition to Zone 2 began with Cell Death and Disease (21 publications) and European Review for Medical and Pharmacological Sciences (21 publications), indicating a drop in publication frequency. These results reflect the concentration of research dissemination within a selected group of highly influential journals in this field.

3.5. Top-recognized documents

The top-cited research in the field of miRNAs in hematological malignancies includes significant studies [ 1 – 3 , 14 , 26 – 31 ] that have advanced our understanding in this area (Table 2 ). Calin et al identified an miRNA signature associated with the prognosis and progression of chronic lymphocytic leukemia. His work with Liu revealed distinct miRNA signatures in B-cell chronic lymphocytic leukemia, contributing to disease characterization. Calin highlighted that human miRNA genes frequently occur at fragile sites involved in cancer development. Cimmino et al demonstrated that miR-15 and miR-16 induce apoptosis by targeting BCL2, suggesting their therapeutic implications. Costinean et al explored miR-155’s role in lymphoblastic leukemia in transgenic mice. Iorio et al investigated miRNA dysregulation in breast cancer, broadening their impact on solid tumors. Landgraf et al created a mammalian miRNA expression atlas to enhance the understanding of miRNA distribution. Leggett and Whitehall examined the role of the serrated pathway in colorectal cancer pathogenesis. Ley et al detailed the genomic and epigenomic landscape of AML. Sempere et al identified brain-expressed miRNAs, suggesting their role in neuronal differentiation. These studies underscore the foundational and emerging concepts in miRNA research.

3.6. Conceptual structure and dynamicity

3.6.1. Word cloud and thematic structure

Conceptual structure and dynamicity in research on miRNAs in hematological malignancies are often examined using co-word analysis, which identifies and maps the relationships between frequently occurring terms or keywords. This approach helps reveal key themes, emerging trends, and evolving focus within the field. By analyzing the co-occurrence of terms in the literature, researchers can understand how concepts are interconnected, track the development of new research areas, and shift priorities over time. [ 21 , 32 ] The most frequent author’s keywords (Fig. 4 ) in research on miRNAs in hematological malignancies included “acute myeloid leukemia” with 402 occurrences, followed by “multiple myeloma” (350 occurrences) and “microRNA” (311 occurrences). Other prominent terms are “prognosis” (168 occurrences), “AML” (159 occurrences), “apoptosis” (158 occurrences), “miRNA” (136 occurrences), and “proliferation” (109 occurrences). Keywords such as “chronic lymphocytic leukemia” (74 occurrences), “biomarker” (73 occurrences), and “leukemia” (64 occurrences) also appear frequently, indicating core areas of focus and common themes in the literature. Further recurring terms include “cancer,” “Chronic Lymphocytic Leukemia,” “exosomes,” and “drug resistance.” Thematic mapping analysis was used to understand the density and centrality of the research domains related to miRNAs in hematological disorders. Centrality measures the strength of links between themes and other research domains, while density indicates the composition of major themes. This analysis revealed the structure and interconnectedness of the research topics, enabling the identification of mature, core, and growing areas. The thematic analysis identified 7 major themes.

Cluster 1 focuses on AML and related processes, including apoptosis, proliferation, autophagy, cell cycle regulation, and specific elements such as mir-34a, PTEN, and BCL2, as well as mechanisms such as migration, invasion, and bioinformatics analysis (motor theme).

Cluster 2 centers on prognosis, with emphasis on lncRNA, gene expression, diagnosis, methylation, chemotherapy, survival, and ceRNA interactions (basic theme).

Cluster 3 is the largest and includes multiple myeloma, miRNAs (miRNA, miR-21, and miR-155), CLL, biomarkers, leukemia, cancer, DNA methylation, exosomes, drug resistance, and epigenetics. This cluster includes key biological pathways and elements, such as p53, bortezomib, differentiation, extracellular vesicles, circular RNA, and related genetic and molecular aspects of hematological malignancies (Basic theme).

Cluster 4 focuses specifically on DLBCL (Niche theme).

Cluster 5 highlighted biomarkers and tumor-suppressor elements in cancer research (basic themes).

Cluster 6 addresses pediatric AML (Niche theme).

Cluster 7 encompasses aspects of cell proliferation and metastasis (Niche theme).

Thematic mapping analysis was used to understand the density and centrality of the research domains related to miRNAs in hematological disorders. Centrality measures the strength of links between themes and other research domains, while density indicates the composition of major themes. This analysis revealed the structure and interconnectedness of the research topics, enabling the identification of mature, core, and growing areas.

3.6.2. Thematic dynamicity

The thematic dynamicity of research on miRNAs in hematological malignancies, as depicted in Figure 5 , illustrates how key themes have evolved over time. From 2003 to 2016, research primarily focused on foundational topics, such as AML, multiple myeloma, biomarkers, miRNA, bortezomib, and various types of lymphomas. During the 2017 to 2021 period, these themes expanded, with AML, multiple myeloma, and biomarkers continuing as central topics, while additional focus was placed on miRNAs and emerging subtopics, including chronic lymphocytic leukemia, mesenchymal stem cells, and chemotherapy. The most recent theme period (2022–2024) shows a move toward deeper molecular and clinical elements, including drug resistance, immunological intrusion, migration, exosomes, acute lymphoblastic leukemia, and enhanced therapeutic techniques such as targeted chemotherapy. This evolutionary path shows a widening of study topics, where more specialized and translational research on the subject results from earlier basic investigations. This development emphasizes the growing complexity and attention of unique and creative treatment strategies.

3.6.3. Emerging topics

Figure 6 highlighted emerging themes in research on miRNAs in hematological malignancies that have gained prominence since 2016. Key themes included ferroptosis, immune infiltration, autophagy, angiogenesis, ceRNA network, disease progression, exosomes, diagnosis, machine learning applications, prognosis, AML, multiple myeloma, apoptosis, and miRNA. These themes reflect the evolving focus on novel mechanisms, diagnostic tools, and therapeutic strategies.

3.7. Co-citation analysis

Co-citation analysis of the authors was conducted using VOSviewer (Fig. 7 ), mapping 49 authors with a minimum of 500 co-citations into 3 clusters: red, blue, and green. Calin, G.A., with the highest TLS (TLS = 41,982) anchored the green cluster. Wang, Y., led the red cluster with a TLS of 35,563, while Anderson, K.C., anchored the blue cluster with a TLS of 14,758. This further emphasizes their significant contributions and influences within their respective thematic groups in the co-citation network.

4. Discussion

miRNAs are involved in the regulation of gene expression, and their epigenetic or genetic modifications have been associated with plasma disorders such as leukemias, lymphomas, and myelodysplastic syndromes. The recent surge in the number of articles/events in relation to miRNAs in hematological malignancies is attributed to the significance of these molecules in gene expression and regulation of cancer transformation, therapy, and diagnosis. Molecular biology and sequencing have provided new concepts and tools, and the quest for novel applications of miRNAs as clinical markers of recurrence and treatment targets has initiated many studies. The combination of intense competition, new technologies, and financial backing has led to this rapid emergence. [ 11 , 33 – 35 ] The present study coincides with this expansion of research, as it distinctly demonstrates that research activity in this field commenced in 2003 and has continued to rise over the years. Since the initiation of hematological malignancy-focused miRNA research in 2003, the field has witnessed a sharp rise in the number of publications generated at a rate of 27.41% annually. This analysis lends credence to earlier bibliometric analyses that claim an increase in the study of miRNAs across different fields of biology and medicine, particularly hypertension, [ 36 ] glaucoma, [ 19 ] stroke, [ 18 ] and bioinformatics tools. [ 37 ]

The concern with participating countries standing at only 37.6%, for example, the 73 representatives to the study, suggests that miRNAs in hematological malignancies have not received as much attention as their impact may suggest. This relatively low number suggests that interest in and contributions to this field are concentrated among a smaller group of countries, primarily those with strong biomedical research infrastructure and resources. Although China, the USA, and Italy are among the top contributors, it is clear that international involvement is not as high as desirable, which may be due to issues such as research funding, infrastructure, and advanced technologies. Global interest and collaboration in this field are likely to lead to more discoveries, better understanding, and further expansion of miRNA research in relation to hematological malignancies. According to prior bibliometric studies, China and the USA are at the forefront of molecular biology research on cancer. [ 38 – 40 ]

Scientific research is becoming a team’s endeavor. The characteristics and extent of collaboration differ among disciplines and are influenced by factors such as research challenges, research environment, and demographic variables. Previous studies have demonstrated a significant association between cooperation and research output, as well as between collaboration and financial support for research. [ 41 ] Global cooperation in microbiome research in hematological malignancies is represented by a worldwide miRNA co-authorship rate of 23.96%. TLS, developed with the help of VOSviewer, has been used to quantify the level of collaboration between countries. The US came first with 640 TLS (Fig. 2 B). Multiple prior studies have highlighted the United States’ preeminence in global medical research collaboration, corroborating our findings. [ 36 , 38 , 39 , 42 ]

Calin et al and Ley et al could be regarded as cornerstone studies in the field of miRNAs and hematological malignancies, as they play a pivotal role in many citations and thus represent important progress in this field of research. According to Calin et al, human miRNA genes are often found in fragile sites and known cancer regions of the genome, such as loss of heterozygosity and amplification. Their study showed that 52.5% of the mapped miRNAs were within cancer-associated regions, suggesting that these miRNAs may play an important role in cancer. This study also showed that many of the miRNAs within the regions that were deleted in the cancer samples showed decreased expression, and thus these miRNAs are involved in tumorigenesis as potential tumor suppressors or oncogenes. This discovery prepared the stage for further tests that aimed to understand the regulatory and diagnostic functions of miRNAs in the context of their application as antineoplastic agents. [ 2 ] Ley et al performed in-depth genomic and epigenomic studies on adult de novo AML using whol-genome and whole-exome sequencing techniques. [ 30 ] Mutations in AML genomes were found to be fewer than those in other adult malignancies, but pinpointed certain genes known to be of significance and recurrently mutated in the setting of the evolution of AML. Derived from their categorization of mutations as involving general classes of functional significance, transcription factor fusions, tumor-suppressor genes, and dna-methylation-associated genes, Ley et al discovered disturbed genetic hierarchies and the role of their interactions in the advancement of the disease. The results of this study provide a proper background to advance the scientific discourse on the pathogenesis of AML, the identification of possible driver mutations, and specific measures of therapeutic interventions. Generally, these studies have set a background for further research by determining the role of genetic and epigenetic abnormalities in the genesis of cancers. Cancer’s developmental and comorbid miRNAs were identified as key components of regulation, Comorbid Ley taking the subject of AML, who offered perspectives on targeted therapies, biomarkers and precision medicine in the context of hematological malignancies. Providing a sound basis for the development of targeted targeting strategies, these drugs started at once and their contributions strive the same line as those of others.

Author co-citation analysis examines the frequency with which 2 or more authors are cited together in different publications. It reveals thematic clusters, key contributors, intellectual communities, and collaborations within the research field. Authors who are frequently co-cited often share related topics or have complementary influences. High co-citation counts indicate a significant impact, whereas network analysis can reveal emerging trends, collaborations, and thematic proximity between authors. This method maps a field’s intellectual structure and highlights influential figures and evolving research areas. [ 20 ] Calin, G.A., with the highest total link strength (TLS = 41,982) anchored the green cluster. Calin is a leading miRNA in hematological malignancies, focusing on its roles in cancer development, prognosis, and therapy. They demonstrated the tumor-suppressive and apoptosis-regulating functions of the miR-15a and miR-16-1 cluster in leukemia. [ 43 ] Calin and Croce highlighted the clinical relevance of miRNAs in CLL genomics. [ 44 ] He identified a miRNA signature linked to prognosis and progression in CLL [ 1 ] and discovered alterations in ultraconserved regions encoding non-coding RNAs in leukemias and carcinomas, connecting these changes to cancer biology. [ 45 ] Calin characterization of distinct miRNA signatures for B-cell CLL provided insights into disease classification, [ 26 ] and he demonstrated that miRNA genes are often located at fragile cancer-related sites. [ 2 ] He coauthored research showing that miR-15 and miR-16 target BCL2 to induce apoptosis, suggesting therapeutic avenues. [ 3 ] This collaboration revealed miR-155’s impact on B-cell receptor signaling and disease aggressiveness in CLL. [ 33 ] Calin identified a miRNA/TP53 feedback loop affecting CLL pathogenesis and patient outcomes [ 34 ] and demonstrated miR-155’s prognostic significance in B-cell lymphocytosis and CLL. [ 35 ] His work on miR-29b highlighted its role in AML, [ 11 ] and examined miRNA signatures and cytogenetics in AML. [ 46 ] He expanded the understanding of miRNA dysregulation in breast cancer [ 27 ] and showed that TCL1 expression in CLL is regulated by miR-29 and miR-181. [ 9 ] Finally, Calin developed an miR-21 score to stratify early survival in patients with CLL, [ 47 ] showing the clinical utility of miRNAs in disease management and prognosis.

Anderson, K.C. led the blue cluster, contributing significantly to research on miRNAs in multiple myeloma. Amodio et al demonstrated that miR-29b sensitizes multiple myeloma cells to bortezomib-induced apoptosis through a feedback loop involving the transcription factor Sp1. [ 10 ] Cirstea et al highlighted the anti-multiple myeloma effects of the kinase inhibitor RGB-286638 through both P53-dependent and independent pathways. [ 8 ] Di Martino et al provided evidence for synthetic miR-34a mimics as therapeutic agents for multiple myeloma, both in vitro and in vivo. [ 48 ] Jagannathan et al explored miR-29b replacement to inhibit proteasomes and to enhance the efficacy of bortezomib by disrupting aggresome-autophagosome formation. [ 13 ] Lawasut et al focused on decoding the pathophysiology and genetics of multiple order to identify novel therapeutic targets. [ 49 ] Leone et al investigated the ability of miR-21 to inhibit multiple myeloma cell growth in vitro and in vivo. [ 50 ] Roccaro et al showed that bone marrow mesenchymal stromal cell-derived exosomes facilitate multiple myeloma progression, while their earlier work [ 51 ] revealed that miRNAs 15a and 16 regulate tumor proliferation. Tian et al studied the investigational agent MLN9708/2238 and its targeting of the tumor-suppressor miR-33b in multiple myeloma cells. [ 52 ] Zhao et al demonstrated that targeting the miR-221-222/PUMA/BAK/BAX pathway can overcome dexamethasone resistance in multiple myeloma. [ 53 ] This body of research underscores the pivotal roles of miRNAs in multiple myeloma pathogenesis and therapy.

The transmutation of the scope of research on miRNAs in hematologic malignancies traces a lively movement in the field from pioneering studies to sophisticated real-world applications. Initially, interest was in core diseases such as AML, multiple myeloma, and other forms of lymphomas centered on miRNA functions, biomarkers, and treatment mechanisms between 2003 and 2016. [ 1 – 3 , 26 , 27 , 31 ] This groundwork has paved the way for broader exploration from 2017 to 2021, where studies have expanded to include chronic lymphocytic leukemia, [ 7 , 16 , 54 – 56 ] mesenchymal stem cells, [ 5 , 15 , 57 ] and chemotherapy [ 4 , 58 , 59 ] approaches, delving deeper into miRNA regulatory networks. In the last 2 years, from 2022 to 2024, the trends have engulfed more into advanced technical and clinical applications directed at drug resistance, [ 17 , 60 ] immune infiltration, exosomes, and other precision therapies for cancer, such as targeted chemotherapy. [ 6 , 61 ] These shifts represent the marked evolution in the increasing role and complexity of miRNAs in the field of precision medicine and new treatment modalities and illustrate great and continuous efforts to improve the quality of life of patients with hematological malignancies.

Figure 6 highlighted emerging themes in research on miRNAs in hematological malignancies that have gained prominence since 2016. The key themes include ferroptosis, immune infiltration, and autophagy. Since its discovery in 2012, ferroptosis has garnered significant interest as a novel mechanism of cell death. The pathological features of ferroptosis, including diminished or absent cristae, membrane concentration, outer membrane rupture, and smaller size, are mostly observed in the mitochondria. At the molecular level, intracellular iron overload and the generation and accumulation of reactive oxygen species cause ferroptosis. [ 18 ] Research indicates that miRNAs can control ferroptosis through interactions with mRNA. [ 62 ] miRNAs influence glutamate/cystine transport to modulate glutathione synthesis, iron metabolism to control intracellular iron levels, lipid metabolism to manage reactive oxygen species production, and other oxidative stress pathways. Ferroptosis-associated miRNAs play several roles in tumor metastasis, including the regulation of tumor cells, immune cells, angiogenesis, and cytokine release. [ 62 , 63 ] In addition to ferroptosis, immune infiltration is a trending topic. Immune infiltration is a term used to describe the penetration of various lymphocytes, macrophages, and other immune components into tumor tissues and the microenvironment surrounding the tumor. Regarding hematological malignancy and miRNAs, immune infiltration is considered important to study because it has been shown that these leukocytes can affect tumor progression and the immune system of patients with tumors. Research has demonstrated that functional miRNAs can regulate the behavior of immune cells, blocking the signaling pathways of immune therapies, in addition to the immunosuppressive milieu that promotes tumors, making immune infiltration a crucial element in cancer prognosis, healing, and the advancement of immunology-based treatments. Mechanistic understanding of immune infiltration and its control by miRNAs provides new options for rationally designed and individualized cancer therapies. [ 5 , 40 , 55 ]

4.1. Comparative context with WHO/ICC classifications

Our findings also merit consideration in light of international classifications of hematopoietic neoplasms. While numerous miRNA alterations have been described in the literature, only a limited subset has been consistently acknowledged in formal classifications. For example, the WHO 4th edition made only passing reference to deregulated miRNAs, reflecting their emerging but unvalidated role at the time. [ 64 ] The recent WHO 5th edition and the International Consensus Classification (ICC, 2022) provide a more detailed overview of genetic lesions but still do not formally list miRNAs as defining abnormalities; instead, emphasis remains on well-established molecular markers such as NPM1 , CEBPA , and TP53 mutations. [ 65 , 66 ] This contrast highlights the gap between the wealth of experimental data demonstrating miRNA dysregulation (e.g., miR-15a/16-1 in chronic lymphocytic leukemia and miR-29b in AML) and their current omission as recognized diagnostic criteria.

4.2. Future perspectives for integration of miRNAs

Looking ahead, several prerequisites are necessary for miRNAs to be incorporated into international classifications as defining genetic abnormalities, similar to NPM1 or CEBPA mutations. First, reproducible evidence from large, multi-center studies must demonstrate consistent diagnostic, prognostic, or predictive value. Second, strong clinicopathological correlations are required to establish clear links between specific miRNA alterations and disease subtypes or clinical outcomes. Third, therapeutic evidence (such as successful targeting of miRNA pathways through mimics, inhibitors, or exosome-mediated delivery) must support their clinical utility. Finally, technical advances are needed to standardize miRNA detection platforms, ensuring reliability and comparability across laboratories. Meeting these requirements could pave the way for miRNAs to become integral components of future disease classifications, bridging the gap between molecular discovery and clinical implementation. [ 12 , 43 , 65 ]

5. Limitations

The limitations of this study include linguistic bias, because it only considers English-language publications and its sole dependence on the Scopus database, which may cause it to ignore research from other fields. Additionally, depending too much on 1 data source may leave important information from other sources. Traditional analytical methods may be supplemented by other types of studies. Future research may use more databases for a more comprehensive analysis, and it is crucial to update the study frequently to include new papers from databases. To gain a better understanding of research trends in this area, the study concludes by suggesting improving the search technique through the use of a multimethod approach or search strategy optimization.

6. Conclusions

By integrating VOSviewer and Biblioshiny, this study conducted a comprehensive multidimensional analysis of the miRNA research landscape in hematological disorders. This study discusses the challenges anticipated in understanding the role of miRNAs in cancer in the future. First, it is extremely important to assess certain molecular targets of miRNAs in relation to cancer, which explains their role in the neoplastic process. In addition, an increased number of studies are required to identify miRNA candidates through deep sequencing and validate them as diagnostic and prognostic markers in large populations, thus demonstrating their role in clinical practice. There are also challenges in using miRNA-based therapies, such as confirming the targets for the therapies to ensure that the correct biological pathways are targeted and to predict and prevent any unintentional off-target reactions. Moreover, creating effective methods of delivery is also important to ensure that the targeted cells receive the intended miRNA therapeutics. There has also been emerging evidence that exosomal miRNAs may be useful as biomarkers, but these are still in the nascent stages of discovery and development and require detailed investigation into their clinical significance. Overall, active and systematic research is required to explore new miRNAs at the translational level, understand how they work, and their genes to enhance the understanding of miRNAs in tumorigenesis and consequently contribute to the development of miRNA-based cancer prediction, diagnostics, and therapies.

Author contributions

Conceptualization: Saleh M. Abdullah.

Data curation: Saleh M. Abdullah.

Formal analysis: Saleh M. Abdullah.

Funding acquisition: Saleh M. Abdullah.

Investigation: Saleh M. Abdullah.

Methodology: Saleh M. Abdullah.

Project administration: Saleh M. Abdullah.

Resources: Saleh M. Abdullah.

Software: Saleh M. Abdullah.

Supervision: Saleh M. Abdullah.

Validation: Saleh M. Abdullah.

Visualization: Saleh M. Abdullah.

Writing – original draft: Saleh M. Abdullah.

Writing – review & editing: Saleh M. Abdullah.

Abbreviations: AML acute myeloid leukemia BCL2 B-cell lymphoma 2 CLL chronic-lymphocytic leukemia DLBCL diffuse large B-cell lymphoma MCP multiple-country publications miRNAs microRNAs SCP single-country publications TLS total link strength

The authors have no funding and conflicts of interest to disclose.

Ethical approval is not required for this study because it does not involve human subjects.

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

How to cite this article: Abdullah SM. Role of microRNAs in hematological malignancies research: A bibliometric analysis. Medicine 2025;104:51(e46688).

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