2.1. Chronic Lymphocytic Leukemia

Chronic lymphocytic leukemia (CLL) is the most common leukemia in adults over 50 (30% of all leukemia cases). It is a lymphoproliferative disorder classified as a low-grade non-Hodgkin lymphoma (NHL). B-cell CLL (B-CLL) accounts for 7% of non-Hodgkin lymphoma cases [19]. It is characterized by the excessive proliferation and subsequent accumulation of mature clonal B lymphocytes in the peripheral blood, bone marrow, lymph tissues, and spleen [20]. About 80% of B-CLL cases present chromosomal abnormalities. The most frequent chromosomal abnormalities include del (13q14.3) in about 50–60% of the cases, del (11q22) in approximately 25% of the cases, del (17p13) in around 5–8% of patients, and trisomy 12 [21]. Besides, various mutations detected in B-CLL cases lead to aberrant expression of some proteins, including mutations in NOTCH1, TP53, C-FOS, C-MYC, ATM, BCL2, TCL1, MYD88, SF3B1, STAT3, and BIRC3 genes [19, 22, 23]. These genetic abnormalities are highly associated with CLL pathogenesis, prognosis, relapse, and drug resistance [23]. However, about 20% of CLL cases do not show chromosomal abnormalities [24]. CLL naturally is an indolent disease with a chronic clinical course; still, several patients are drug resistant and relapse with conventional chemotherapy or innovative targeted therapies and immunotherapies [23]. It has been reported that ncRNA modifications may affect disease outcomes [25].

2.2. B-Cell Lymphoma

Mature B-cell neoplasms are responsible for more than 80% of NHL. Diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma are the most common types, comprising more than half of all NHL cases [26]. Mature B-cell neoplasms include various malignancies with different genetics, phenotypes, morphology, and clinical manifestations. This lymphoid malignancy can affect peripheral lymph nodes and organs such as the liver, lungs, and bone marrow [27]. Similarly, NHL lymphomas are heterogeneous neoplasms that vary in biological markers, clinical behaviors, and prognosis. This type of lymphoma mainly originates from B-cells; however, 10% develop from T lymphocytes [28]. Hodgkin lymphoma (HL) has a nearly 80–90% chemotherapy response rate among all lymphomas [29]. However, 15–20% of the patients who suffer from HL develop resistance to chemotherapy drugs or show recurrence within two years after initiating treatment [30]. Furthermore, despite significant advances in chemotherapy, more than half of B NHL patients do not respond to conventional therapies [31].

2.3. Treatments

Optimal management of relapsed/refractory B-cell lymphoma and CLL patients depends on patient characteristics, the prior treatment, and their response. Increasing the rate of disease-free survival and providing the chance of long-term progression-free survival can only be achieved through the novel therapeutic agents’ route. Although most patients respond to chemotherapy (including fludarabine and cyclophosphamide), finding favorable therapeutic interventions for relapsed and refractory patients is still challenging. Other treatment choices include hematopoietic stem cell transplantation, targeted immunotherapy, and inhibitors [32].

Hematopoietic stem cell transplantation (HSCT) is the only suggested curative therapy for B-cell malignancies, though it is not accessible to most patients and has significant associated risks [33]. CLL cases are prone to show graft versus leukemia following allogeneic HSCT, resulting in durable remissions in 30–50% of the cases. However, it may cause graft-versus-host disease, infection, and nonrelapse mortality. Despite the promising application of HSCT in high-risk CLL cases, its usage has decreased over the years due to emerging innovative targeted treatments [34].

B-cell differentiation antigens (CD19, CD20, and CD22) provide an ideal opportunity for specific targeted therapy. Targeting CD20 using monoclonal or conjugated antibodies is one of the earliest strategies in targeted immunotherapy, which is currently prescribed as a part of standard-of-care regimens for CLL and B-cell lymphoma. CD19, CD22, and CD38 received special attention for immunotherapy applications. Targeted therapies such as ibrutinib (Bruton’s tyrosine kinase inhibitor), venetoclax (Bcl-2 inhibitor), and idelalisib (phosphoinositide 3-kinase inhibitor) have made a significant impact on leukemia and lymphoma treatment [35].

Chimeric antigen receptor T (CAR-T) cell therapy is one of the most effective treatments for refractory/relapsed hematological malignancies. CARTs are cells collected by leukapheresis and genetically modified by transferring the chimeric antigen receptor gene. Following the ex vivo expansion, CAR T cells were infused into the patient to target the specific antigen of interest in malignant cells [36, 37].

Induction of the B-cell receptor (BCR) signaling pathway and dysregulation of the apoptosis are pathophysiologic hallmarks of CLL [38]. Thus, therapeutic agents targeting the BCR signaling (ibrutinib, idelalisib, and duvelisib) and Bcl2 inhibitors (venetoclax and acalabrutinib) are promising therapeutic strategies for CLL management [23]. A novel treatment option targets BCR signaling by Bruton’s tyrosine kinase (BTK) inhibitor, like ibrutinib [39, 40].

Programmed death 1 (PD-1) immune checkpoint and its ligands (PD-L1/L2) are crucial in tumor evasion. Their overexpression is associated with tumor progression and prolonged survival. Hence, targeting PD-1 with anti-PD-1 antibodies can reduce the progression rates and improve survival [41].

2.4. Drug Resistance

Cancer cells acquire resistance to chemotherapy drugs through various mechanisms. Drug resistance in leukemias mostly happen due to mechanisms such as drug efflux, reduced drug uptake, changes in drug metabolism, and epigenetic modifications [5]. For instance, interfering with both intrinsic and extrinsic apoptosis pathways is one of the strategies tumor cells use to develop resistance against chemotherapy drugs [42]. Cell apoptosis occurs due to various factors ranging from external mediators, such as death signals from death receptors to the internal disturbance in the balance of apoptotic pathway proteins, such as the Bcl2 family, in response to unbearable cell conditions. Severe stress conditions, widespread DNA damage, overactivation of oncogene proteins, and lack of sufficient growth signals within the cell environment are the primary triggers in the induction of apoptosis [43]. The findings from experimental evidence show that the dysregulation of apoptotic and antiapoptotic mediators is essential in developing drug resistance in cancer patients. For instance, an increased expression of antiapoptotic proteins in the Bcl2 family is crucial in developing drug resistance in NHL [44]. Considering the role of cell cycle regulators in cell proliferation, changes in the expression of these mediators and signaling pathways that overlap with them are crucial in drug resistance. According to reports, the sensitivity of cancer cells to chemotherapy drugs varies in different phases of the cell cycle. Hence, the most remarkable outcomes in chemotherapy will be achieved when cancer cells are in the S phase, where cells experience the most vulnerable period in the cell cycle stages [45]. Oncogenes are a group of genes coding for proteins that regulate the vital activities of cells. A wide range of mediators, such as growth factors, growth factor receptors, cell cycle regulators, and transcription factors, fall into the oncogene category [46]. So far, many studies have highlighted the fundamental part of oncogenes in cancer cell drug resistance [47]. Considering the critical role of such mediators in the response of lymphoma cells to chemotherapy drugs, they have become potential targets for neoplasm treatment [48].

3.1. microRNAs

miRNAs, as the leading group of ncRNAs, comprise 21–25 nucleotides [53]. In recent years, given the critical role of miRNAs in various biological events, special attention has been paid to them. miRNA develops a recognition machine to find and cleavage the target mRNA, which is the leading way that miRNAs regulate the gene expression of their targets at the translational levels [54]. It implies the importance of these regulator molecules in different biological pathways, so any alteration in the delicate balance of miRNA expression may lead to severe pathological conditions, including cancer [55]. In recent years, the direct relationship between the dysregulation of different miRNAs and various cancer types has been well documented in the literature [56]. As observed in malignancies, chromosomal instabilities, changes in transcription levels, and epigenetic alterations profoundly affect the expression patterns of miRNAs in cancer cells [57].

3.2. Long Noncoding RNAs

lncRNAs are transcripts more than 200 nucleotides in length [58]. LncRNAs are involved in biological pathways such as gene expression, apoptosis, and carcinogenesis [59]. Studies indicated the diverse role of lncRNA in cell differentiation and tissue development via transcriptional and posttranscriptional regulation [60]. LncRNAs are involved in the pathogenesis, metastasis, and drug resistance in leukemia via mutations, chromosomal translocations, and epigenetic regulation [61]. Besides, lncRNAs are involved in cell cycle and cancer invasion, either as tumor suppressors or oncogenes [62]. Moreover, lncRNAs influence crucial factors in lymphocyte development, such as NOTCH, PAX5, and MYC. They can modulate lymphocyte activation by regulating signaling pathways such as TCR/BCR signaling, NFκB, and NFAT [63].

4.1. Apoptosis, Oncogenes, and Tumore Supressors

As described in the previous sections, miRNAs can alter cell metabolic activity by changing various cellular mechanisms that ultimately affect cell proliferation rate and response to environmental cues. Numerous studies have shown a significant change in the miRNA profile of cancer cells that influences the vital biological pathways involved in cancer development and progression, such as apoptosis [57]. This section will discuss the relationship between miRNA dysregulation and changes in the expression of various mediators involved in apoptosis, as the primary chemo-drug resistance mechanism, in both HL and NHL lymphoma.

DLBCL, a type of NHL, is still hard to treat, so efforts are underway to find the mechanism involved in tumor progression and drug resistance [112]. Recent studies have highlighted the role of miRNAs in the expression of apoptotic effectors that consequently alter the response to therapy in this cancer type [113]. For example, the downregulation of proapoptotic proteins such as Bax and caspase-3 has been reported in samples obtained from DLBCL patients. Due to the apparent overexpression of miR-155 in the tumor samples compared with normal adjacent tissues, the mRNA of the proapoptotic proteins were suggested as the possible targets of this miRNA. Zhu et al. evaluated the importance of miR-155 by transfecting OCI-Ly3 and Rose cells with anti-miR-155 and miR-155 mimics. They reported a notable increase in the Bax/Bcl-2 ratio and caspase-3 expression in the anti-miR-155 transfected cells, while a reverse pattern was observed in those transfected by miR-155 mimics [91].

Bcl-2, the founding member of the Bcl-2 family, is an antiapoptotic protein that prevents mitochondrial membrane permeability [114]. Bax, another member of the Bcl-2 family, increases mitochondrial membrane permeability by opening voltage channels [115]. The apoptotic cascade will be activated by cytochrome c released from mitochondria and finally causes DNA cleavage through caspase-3 activation. Studies revealed the undeniable role of Bcl-2 family proteins in developing resistance to chemotherapy drugs and opened a new avenue in applying them as prognostic factors in DLBCL lymphoma. miRNAs influence the expression of these proteins at both transcriptional and translational levels. Recently, miR-21 has been introduced as a strategic element in developing resistance to chemotherapeutic drugs in lymphoma. There is a significant correlation between miR-21 and Bcl-2 in the tumor samples obtained from DLBCL patients. The relationship was further analyzed by transfection of miR-21 mimics into the OCI-LY3 cell line, where an overexpression of Bcl-2 protein was observed. miR-21, via direct targeting of the 3′-untranslated region (3′UTR) of Bcl-2, elevated its expression through an unknown mechanism. Consequently, miR-21 indicated a poor prognostic feature in DLBCL by increasing Bcl-2 protein expression, leading to acquired resistance to chemotherapy drugs. However, more investigations are needed to clarify how miR-21 regulates Bcl-2 expression in DLBCL tumor cells [116].

Based on a bioinformatic study, among the targets of miR-148b, BCLw is one of the most important ones that any changes in its expression affect tumor cell response to radiation. In this regard, a study by Liu et al. investigated the role of miR-148b in inducing sensitivity to radiation in B-cell lymphoma cells and reported that irradiated cells expressed higher miR-148b and lower BCLw. Forced expression of miR-148b in irradiated cells effectively reduced cell growth and colony formation. Moreover, the mice that subcutaneously received Raji cells containing miR-148b mimics showed a smaller tumor size than those with Raji cells transfected with miR-148b inhibitors [87]. A study investigated the role of four distinct miRNAs, including miR-467a, miR-762, miR-455, and miR-455, in radiation-induced mouse thymic lymphoma. It reported that miR-467a expression in thymic lymphoma cells was four times higher than in normal cells. An in silico study suggested FAX and BAX proteins as the main targets of miR-467a. The overexpression of miR-467a in tumor cells notably increased cell proliferation and colony formation while remarkably decreasing the apoptosis rate. A study on EL4 and NIH3T3 mouse cell lines transfected by miR-467a mimics revealed decreased expression of FAX and BAX proteins. Thymic lymphoma cells are suggested to respond to radiation therapy by overexpressing miR-467a, which induces drug resistance by decreasing proapoptotic mediators such as FAX and BAX proteins in the irradiated cells [86].

Bcl6 is another protein member in the Bcl-2 family with an antiapoptotic role [117]. Huang et al. reported the role of miR-187-3p in regulating Bcl6 expression in DLBCL cells. miR-187-3p binds to the 3′ UTR region of Bcl6 mRNA, suppresses it, and reduces its translation. Forced expression of miR-187-3p in the SUDHL2 cell line increased their sensitivity to chemotherapy drugs. Study results suggested that changes in miR-187-3p levels may increase the sensitivity of DLBCL cells to chemotherapy drugs by reducing BCL6 protein expression [90].

Some miRNAs indirectly control apoptotic pathways. Bmi protein is increased in patients with poor prognosis and chemotherapy-resistant cancers. Teshima et al. reported a decreased expression of miR-16, a chief regulator of Bmi protein, in MCL. miR-16 is an upstream regulator of proapoptotic mediators, including Bcl2L11 and Noxa. They showed that up-regulation of Bmi protein due to down-regulation of this miRNA was associated with cancer cell survival resulting from inhibiting proapoptotic proteins [89].

miR-15a/16-1 cluster, linked to 13q14, are negative regulators of antiapoptotic Bcl-2 protein. Thus, 13q14 deletion causes down-regulation of miR-15a/16-1 cluster and consequent overexpression of antiapoptotic gene Bcl-2, resulting in resistance to apoptosis [22, 118]. Since miR-15a and miR-16-1 act as antisense Bcl2 interactors that negatively regulate Bcl-2 at a posttranscriptional level, they can be applied to treat Bcl-2-overexpressing tumors like CLL [118]. Venetoclax, a Bcl-2 inhibitor, shows an 80% response rate even in poor prognostic patients with 17p deletions [91, 119].

Szymczyk et al. assessed the potential of microRNAs as predictive biomarkers in CLL patients who received purine nucleoside analogs (PNA) chemotherapy (fludarabine and cladribine). Patients with higher expression of miR-34a showed a higher PNA-induced apoptosis rate, so they suggested the miR-34a expression as a predictor of apoptosis [120].

As miRNAs regulate the expression of various genes involved in self-renewal, survival, proliferation, differentiation, and apoptosis, their dysregulation can result in oncogenic events. Dysregulated miRNAs involved in malignancies are classified into the following two categories: oncomiRs contributing to tumor-promoting functions and tumor-suppressive miRNAs preventing tumor development by inhibiting oncogenes [121]. In malignancies, oncomiRs are overexpressed, while tumor-suppressive miRNAs are underexpressed. The upregulated oncomiRs target tumor-suppressor genes, leading to their downregulation and cancer. In contrast, tumor-suppressive miRNAs are downregulated in malignancies, resulting in the overexpression of the oncogenes [122]. In this regard, therapeutic strategies focus on controlling these miRNA’s expression, using replacement of the tumor-suppressive miRNAs by mimicking them or inhibiting oncomiRs by anti-miRs [123].

Proto-oncogenes are a group of genes that undeniably impact cell biological behaviors, and their dysregulation contributes to various malignancies. Proto-oncogenes are divided into different categories based on their type of activities, including (i) growth factors, (ii) growth factor receptors, (iii) intracellular signaling mediators, (iv) gene transcription factors, and (v) factors involved in cell cycle regulation [124]. Mutations or any changes in the expression of proto-oncogenes cause them to be converted into oncogenes. Different mechanisms are involved in altering proto-oncogenes into oncogenes, including changes in the number of their encoding genes and dysregulation of proto-oncogenes regulators to elevate the activity or half-life of proto-oncogenes [125, 126]. In lymphomas, proto-oncogenes’ expression and activities have been changed differently in different subclasses. For instance, abnormal activation of the BCR receptor, NFĸB nucleus factor, and JAK-STAT activator are common in activated B-cell (ABC)-lymphoma. In germinal center B-cell lymphoma, however, defects in the function of epigenetically regulated proteins and mutations in the PI3K-AKT signaling pathway are more prevalent. Moreover, the overexpression of signaling pathways such as PI3K-AKT, JAK-STAT, and WNT are frequently reported in MCL, leading to cell proliferation and increased resistance to chemotherapy drugs. miRNAs notably influence the chemotherapy response in lymphomas by regulating a wide range of proto-oncogenes [127].

Previous studies have shown that patients with MCL lymphoma exhibited a gene amplification at 13q31-q32, encoding the miR-17∼92 cluster, which is associated with a poor survival rate. According to a gene expression profile study, miR-17∼92 cluster increased in patients with MCL by overactivating the PI3K-AKT signaling pathway, causing tumor growth and poor prognosis. miR-17∼92 cluster via direct targeting of PHLPP2, the primary negative regulator of PI3K-AKT signaling, increases this signaling pathway’s activity. Overexpression of miR-17∼92 cluster inhibited chemotherapy-induced apoptosis in MCL-derived cell lines. Thus, targeting the miR-17∼92 cluster could be a new therapeutic approach to treating MCL patients [128].

Transcription factors consist of an essential part of proto-oncogene proteins. These factors profoundly affect cellular metabolic activities. Yin Yang1 (YY1) protein controls the various genes involved in cell death, cell cycle, cell metabolism, proliferation, inflammatory responses, and escape from the immune system. Some studies have been conducted on this protein in various cancers, suggesting the dual role of YY1 as an oncogene protein and tumor suppressor [129, 130]. It is reported that there is a direct relationship between the high expression of this transcription factor and the aggressiveness of Burkitt lymphoma. Among the miRNAs associated with the YY1 protein, miR-363 and miR-200a were reduced in Burkitt lymphoma tissues compared with normal tissues. However, more studies are needed to determine the exact correlation between these two miRNAs and the increased expression of YY1 in Burkitt lymphoma. A better understanding of the pathogenesis of this malignancy could be provided by discovering a link between these two factors [130].

Different studies have indicated the role of miR-34a as a proapoptotic and tumor suppressor mediator. SIRT1 enzyme, a direct target for miR-34a, disturbs the function of the TP53 protein through the deacetylation of an amino acid in its structure. Indeed, miR-34a indirectly increases TP53 activity by targeting SIRT1 [131]. Sotillo et al. studied the role of miR-34a in bortezomib-induced apoptosis in four cell lines, including P493-6, GM609, LY47, and Nalm-6. Unexpectedly, the overexpression of miR-34a in Myc-upregulated cell lines decreased the P53 activity in cells treated with bortezomib. They concluded that miR-34a deregulation to increase bortezomib-induced apoptosis had the opposite effect on treating B-cell-derived lymphomas due to targeting P53 [131]. Cerna et al. indicated remarkable miR-34a upregulation induced by DNA damage in CLL during chemoimmunotherapy (fludarabine, cyclophosphamide, and rituximab). miR-34a binds to FOXP1 and suppresses its expression, limiting BCR signaling. Low miR-34a levels are associated with worse response or shorter survival [95].

Downregulation of miR-22 resulting from aberrant activation of the Jak3/STAT signaling pathway has a remarkable impact on the pathogenesis of cutaneous T-cell lymphoma (CTCL). The miR-22 expression decreased in different cancers, such as colon and breast cancers [132, 133]. Sibbesen et al. reported that downregulation of miR-22 elevated the expression of a few oncogene proteins, including MAX, NCoA1, MYCBP, and CDK6, in two distinct cell lines, MyLa2059 and SeAx. They found that STAT5 suppressed the expression of this tumor suppressor miRNA by binding to the promoter of the miR-22 host gene, which actively contributes to the pathogenesis of CTCL [134].

Metastasis is the migration of tumor cells from the primary tumor site to the other tissues, which is usually associated with a poor prognosis and resistance to treatment. Reports have shown that the expression of miR-150 is reduced in the metastatic stage of CTCL as well as T cell and NK cell lymphomas. It is reported that increasing the miR-150 levels reduced tumor metastasis and invasion in the NOD/SCID mice model by targeting the C-C chemokine receptor type 6 (CCR6). miR-150 prevented the CCR6 binding to its ligand (CCL20) in the advanced stages of CTCL by reducing the expression of CCR6 [103]. The exact mechanism of miR-150 downregulation in such malignancies is not elucidated yet. However, epigenetic changes are thought to be involved in the downregulation of this miRNA.

Leivonen et al. found a difference in the miRNA pattern between patients with DLBCL and those who relapsed after chemotherapy. They found that the expression of 13 miRNAs involved in MAPK and BCR signaling pathways differed in the two groups of patients. Further evaluations showed that overexpression of miR-370-3p, miR-381-3p, and miR-409-3p in the SU-DHL-4 cell line decreased the expression of PI, MAPK, and BCR, leading to an increased sensitivity to chemotherapy agents [104].

Mraz et al. conducted a cohort that assessed the expression of 35 miRNAs, frequently discussed in lymphocyte development and CLL biology. They concluded that miR-34a, miR-29c, and miR-17 are downregulated in CLL cases with TP53 abnormalities [135]. Pekarsky et al. reported a higher expression of miR-29 oncomiR in CLL cases than in healthy individuals. Similarly, the well-known oncogene TCL1 was overexpressed in aggressive CLL patients [136].

Low levels of miR-15a and miR-16 due to 13q14 deletion stimulate TP53 upregulation, leading to overexpression of miR-34b-3p and miR-34c, reducing ZAP-70 and its downstream pathways, resulting in indolent B-CLL phenotype [137]. Besides, miR-17∼92 cluster is a critical oncogenic miRNA in CLL pathogenesis and progression. miR-17∼92 cluster is regularly overexpressed in CLL cases and targets various transcripts like PTEN tumor suppressor [138]. miR-17∼92 cluster is a Myc-stimulated cluster and a central BCR signaling regulator that stimulates BCR ligation via ITIMs. miR-17∼92 cluster upregulation in DLBCLs is due to higher expression of Myc [70]. Moreover, oncogenic miRNAs, such as miR-22, miR-34a, miR-146b, and miR-181b, considerably decreased in response to ibrutinib therapy in CLL patients [38]. MYC suppresses miR-29 expression in CLL, which upregulated tumor-necrosis factor receptor-associated factor 4 (TRAF4), increasing CLL responsiveness to CD40 activation and inducing the nuclear factor NF-kappa-B (NFkB) signaling pathway. The CD40-NFkB signaling can be interrupted by BCR inhibitors such as ibrutinib (Tyrosine-protein kinase BTK inhibitor) or idelalisib (PI3K inhibitor) [110].

4.2. Cell Cycle Mediators

The cell cycle process is a highly conserved biological event in that various regulators, including cyclin-dependent kinases (CDKs) and cyclins, are involved in a controlled manner. The relationship between the unbalanced expression of cyclins and CDKs and different types of cancer has been well documented in the literature [139]. According to the study conducted by Wu et al., there is a correlation between resistance against the CHOP regime in patients with DLBCL and downregulation of miRNA-146b and miRNA-320d. By studying 106 primary nodal samples, they found a decrease in the expression of the mentioned miRNAs in patients with a poor prognosis. Further analysis revealed decreased cell proliferation when the DB and OCI-Ly8 cell lines were forced to express miRNA-146b and miRNA-320d. They proposed the p21^Cip1/Waf1 and p27 ^Kip1 as possible targets for the miRNAs. The overexpression of its activator, P35, has also been observed in DLBCL. Evaluating the expression of these regulators in DLBCL cell lines showed CDK5 and p35 overexpression and downregulation of miRNA-26a as the direct regulator of p35. It introduces a new possible strategy for treating DLBCL so that the forced expression of miR-26a in the DLBCL mice model remarkably diminished the tumor growth [81, 106].

Cyclin-dependent kinase inhibitor 1B enzyme (CDKN1B) is a Cip/Kip family member that prevents cells from progressing from the G1 phase to the S phase by targeting different cyclins and CDKs [81]. Studying Cdkn1b null (p27^−/−) mice revealed a high catalytic function of cyclin A/Cdk2 and cyclin D/Cdk4 in their thymocytes. The delicate regulation of this protein is essential in T-cell development. Recently, the miR-106a∼363 cluster on X-chromosome has been reported to have a pivotal role in developing T-cell lymphomas through direct targeting of the p27^Kip1. In normal T-cell development, the expression of the miR-106a∼363 cluster is downregulated in the CD4+/CD8+ double-positive stage [140]. However, the overexpression of these miRNAs disturbs the normal differentiation of T cells and leads them to form aggressive T-cell lymphomas [107]. Recently, traces of CDKN1B downregulation caused by miR-24-3p in HL have been determined. Accordingly, loss of function analysis introduced the CDKN1B/CDKN1B and MYC proteins as the main targets for the miR-24-3p. Inhibiting the expression of this miRNA in HL cell lines was associated with decreased cell growth and increased apoptosis [79].

Cyclin-dependent kinase inhibitor 1 protein is a cyclin-dependent kinase inhibitor encoded by the CDKN1A gene on chromosome 6. This protein is actively involved in cell cycle regulation by directly targeting different cyclins and CDKs, including CDK4/6, CDK1, and cyclin-CDK2, forcing cells to arrest in the G1 phase [141]. It is reported that miR-17∼92 cluster plays a crucial role in B-cell lymphomagenesis via direct targeting p21^Cip1. However, the targets of miR-17∼92 cluster appear to be varied in different B-cell lymphoma subtypes. Inomata et al. transfected miR-17∼92 cluster into two genetically different B-cell lymphoma cell lines. Accordingly, the transfected Raji cells exhibited low expression of Bim, suggesting this protein is the main target of miR-17∼92 cluster in this cell line. On the other hand, the miR-17∼92 cluster transfected SUDHL4 cells showed decreased CDKN1A/CDKI1, resulting in increased cell growth due to the G1 to S transition in the transfected cells [108].

Cyclin E2 is a protein encoded by the CCNE2 gene. This protein is a G1 cyclin that is functional when it binds to cyclin-dependent kinase 2. The overexpression of this protein has been reported in mucosa-associated lymphoid tissue (MALT) lymphoma. There is an inverse relationship between cyclin E2 and miR-200a, b, and c expression in MALT lymphoma. The results obtained from the luciferase reporter assay confirmed the mRNA of the cyclin E2 protein as the main target of the miR-200 family. Evaluating the expression pattern of conjunctival MALT lymphoma samples showed lower expression levels of the miR-200 family in the tumors than in healthy tissues around the tumor [109].

miR-150 and miR-155 interfere with B-cell development and are involved in CLL pathogenesis. As overexpression of miR-150, a lymphopoietic-specific miRNA inhibits the proB to pre-B transition. Besides, miR-155 upregulation enhanced responsiveness to BCR ligation [92]. Moreover, miR-150 and miR-155 correlated with prognosis and overall survival in CLL cases [138]. miR-155 overexpression was reported to be associated with adverse outcomes in CLL cases [69, 92].

Following BCR activation that appeared to be correlated with remarkably shorter overall survival in CLL patients, all miR-29 family members, including miR-29a, miR-29b, and miR-29c, were constantly downregulated [142].

Arresting in G0/G1 stages and accumulation of the arrested clonal B-cells result in CLL. miR-22 overexpression induces the activation of the PI3K/AKT pathway and downregulation of phosphatase and tensin homolog. The critical role of the PI3K/AKT pathway provides an extra reason for using PI3K inhibitors in CLL [110].

4.3. Monoclonal Antibody-Targeted Therapy

Although single-agent targeted therapy can be highly effective in CLL patients, it may not eliminate the risk of resistance or relapse [143]. Due to miRNA dysregulation, consequences such as drug resistance and relapse have been detected even with novel treatments [144]. Saleh et al. evaluated 38 CLL patients pre-and posttreatment with ibrutinib and observed a significant reduction in a group of miRNAs (miR-22, miR-34a, miR-146b, and miR-181b) in response to ibrutinib. They also indicated a simultaneous increase in presumed miRNA target transcripts, like inhibitor of Bruton tyrosine kinase (IBTK) and PTEN. They concluded that ibrutinib downregulates B-cell activation-related miRNAs, increasing target gene expression like tumor suppressors, which reduce cell proliferation [38]. Zenz et al. reported miR-34a downregulation in fludarabine-resistant CLL cases [145]. In compliance, Rossi et al. indicated that miR-181b expression levels predict treatment-free survival, as its downregulation was seen in therapy-refractory CLL patients [75]. miR-155 and miR-21 can be applied to distinguish fludarabine-resistant CLLs from sensitive cases [144]. ROR1, encoding an oncoembryonic surface protein expressed on CLL cells in more than 90% of the cases, is a newly identified target of miR-15/16 that is highly expressed in CLL cases lacking miR-15/16 cluster. Accordingly, the combination therapy of venetoclax (anti- Bcl-2 mAb) and cirmtuzumab (anti-ROR1 mAb) has an additive effect on CLL management [146].

microRNAs inhibit the PD-1 axis by direct binding to the 3′UTR of PDCD1and PD-1 ligands mRNA [41] or by indirect binding to the PDCD1/CD274, PDCD1LG2 regulators [41, 147]. Zheng et al. indicated that miR155 overexpression in DLBCL enhanced PD-L1 expression, which is associated with poor outcomes [148]. He et al. reported miR-195 downregulation and PD-L1 upregulation in DLBCL tissues; thus, they concluded that overexpressed miR-195 targeted and suppressed the PD-L1 expression [149]. Sun et al. demonstrated miR-214 downregulation and PD-L1 upregulation in DLBCL tissues compared with normal B-cells. They showed that miR-214 targeted PD-L1 mRNA and regulated DLBCL progression [150]. Indeed, as there is a correlation between miR-155, miR-195, and miR-214 with PD-L1 expression, these miRNA levels can be a relapse or refractoriness predictor. Accordingly, PD-1/PD-L1 blockade therapy is revolutionary for treating a broad range of hematologic malignancies. However, only a minority of cases respond positively to this therapy [151]. miRNAs and lncRNAs have a part in resistance to PD-1/PD-L1 blockade therapy. For instance, PD-L1-inhibiting miRNAs include miR-26a, miR-26b, miR-193a, and miR-214 [152].

5.1. MYC

In B-cell malignancies, lncRNAs cooperate with classical oncogenes like MYC. Due to the central role of MYC in cell physiology, it must be precisely regulated. In this regard, it is directly targeted by miR-34 and promotes lncRNA RMRP transcription to absorb miR-34. Because of the constant degradation of MYC via its phosphorylation, its activity decreases as time passes. Therefore, lncRNA PVT1 binds MYC and inhibits its phosphorylation to increase its activity. FIRRE and DANCR lncRNAs play a role in B-cell proliferation by MYC. FIRRE stimulates proliferation by activating WNT/β-catenin signaling pathway, whereas DANCR does it by CDKN1A inhibition. Moreover, lncRNA PDIA3P leads MYC to bind the G6PD promoter to enhance its expression and, subsequently, the pentose phosphatase pathway. On the other hand, lncRNA GAS5 serves as a tumor suppressor by interacting with eIF4E to suppress MYC translation [63].

MYC directly binds to miRNA promotors to suppress tumors’ suppressor miRNAs like miR- 150, miR-15/16, miR-26, and miR-29. Besides, MYC recruits the zeste homolog 2 (EZH2) enhancer to enhance the proliferative program through histone methylation and epigenetic changes [63]. LncRNAs ROR1-AS1 and MALAT1 bind EZH2 to promote cell proliferation in MCL [155, 156]. Besides, EZH2 is associated with apoptosis evasion in B-cell lymphomas by suppressing lncRNA FAS-AS1 [157]. Musilova et al. revealed that high levels of MYC lead to miR-150 downregulation and subsequent high levels of its target, FOXP1, which is associated with shorter overall survival and transformation of follicular lymphoma [158].

5.2. Deletion 13

Genomic aberrations and such alterations in hematological malignancies probably dysregulate lncRNA expression. Hence, lncRNAs are differentially expressed in prognostic subgroups of CLL [63]. CLL’s most common genetic aberration is the deletion of the 13q region, associating two lncRNAs (DLEU1 and DLEU2). DLEU2 is documented as the host gene for the miR-15/16 cluster, and DLEU2 affects the genes involved in the NFkB pathway [159]. Ronchettiet et al. introduced two lncRNAs, lnc-IRF2-3 and lnc-KIAA1755-4, to classify CLL patients into three prognostic groups [160].

5.3. TP53

The TP53 responds to stress and DNA damage accumulation by regulating cell cycle arrest and apoptosis. Following the DNA damage, lncRNAs NEAT1 and lincRNA-p21 are upregulated by TP53 to induce apoptosis. However, their upregulation is impaired in Tp53 aberrant B-cell malignancies, similar to miR-34a, a direct Tp53 target [161].