Journal of Applied Hematology

ORIGINAL ARTICLE
Year
: 2022  |  Volume : 13  |  Issue : 2  |  Page : 76--83

Role of interleukin-10 (1082G/A) and splicing factor 3B subunit 1 (2098A/G) gene polymorphisms in chronic lymphocytic leukemia


Marwa Ahmed Gamaleldin1, Mayada Aly Moussa2, Salma Alaa Eldin Imbaby1,  
1 Department of Clinical Pathology, University of Alexandria, Alexandria, Egypt
2 Department of Internal Medicine, Hematology Unit, Faculty of Medicine, Alexandria University, Alexandria, Egypt

Correspondence Address:
Prof. Marwa Ahmed Gamaleldin
Department of Clinical Pathology, University of Alexandria, Alexandria
Egypt

Abstract

OBJECTIVE: Interleukin-10 (IL-10) gene polymorphisms might play a part in the development of some malignant tumors. It has been linked with high bcl-2 expression in some B-lymphocyte malignancies. Its relationship with chronic lymphocytic leukemia (CLL) development is still under investigation. Other studies have linked Splicing Factor 3B Subunit 1 (SF3B1) mutations to a poorer prognosis of CLL. From this context, we have great interest to investigate the effect of both IL-10 (1082G/A) and SF3B1 (2098A/G) gene polymorphisms on CLL in this study. MATERIALS AND METHODS: Peripheral blood mononuclear cells were analyzed for IL-10 (1082G/A) and SF3B1 (2098A/G) gene polymorphisms by real-time quantitative polymerase chain reaction in 80 newly diagnosed CLL patients and 80 controls. RESULTS: Our results showed that the IL-10 (G/A) genotype, IL-10 (A/A) genotype and IL-10 A allele and SF3B1 (A/G) genotype and SF3B1 G allele were increased significantly in the patients group compared with the control group. CONCLUSION: IL-10 gene polymorphisms (1082 G/A and A/A) and A alleles might be associated with increased risk of CLL development compared with G/G genotypes and G alleles and are a probable risk factor for the disease. Also, our study demonstrated that SF3B1 (2098A/G) polymorphisms and G allele are related to and might be a causative factor for CLL.



How to cite this article:
Gamaleldin MA, Moussa MA, Eldin Imbaby SA. Role of interleukin-10 (1082G/A) and splicing factor 3B subunit 1 (2098A/G) gene polymorphisms in chronic lymphocytic leukemia.J Appl Hematol 2022;13:76-83


How to cite this URL:
Gamaleldin MA, Moussa MA, Eldin Imbaby SA. Role of interleukin-10 (1082G/A) and splicing factor 3B subunit 1 (2098A/G) gene polymorphisms in chronic lymphocytic leukemia. J Appl Hematol [serial online] 2022 [cited 2022 Aug 13 ];13:76-83
Available from: https://www.jahjournal.org/text.asp?2022/13/2/76/353281


Full Text

 Introduction



Chronic lymphocytic leukemia (CLL) is the most common hematologic cancer in developed countries among older adults, comprising around 30% of all leukemias.[1],[2] CLL usually demonstrates a clinical and biological heterogeneous course. Some CLL patients experience an indolent mild course in the early stages requiring no specific treatment, while other patients suffer from an aggressive course not responding to intensive therapy.[3],[4] It is characterized by the unregulated proliferation of monoclonal mature B-lymphocyte cells that are CD19+, CD5+, and CD23+ in the bone marrow and blood.[4] CLL symptoms include fatigue, night sweating, fever, progressive anemia, and progressive thrombocytopenia.[3],[5] It is, thus, of utmost importance to recognize the different factors that could affect the development, prognosis, and treatment of CLL.[4],[6] Certain cytogenetic and molecular mutations, like immunoglobulin heavy chain variable region, have been proved to successfully predict CLL prognosis.[3],[5],[7] However, there is a crucial need for more reliable biomarkers to predict the disease progression and survival more closely.[4]

As more data nowadays point towards the involvement of the genetic factors in the CLL prognosis, cytokine gene polymorphisms now show a high probability as a prognostic factor of CLL.[8] Immunoregulatory cytokines are protein molecules that regulate inflammation, immune reactions, apoptosis, differentiation, and proliferation of lymphocytes.[8] In addition, they have an essential part in the balance between humoral and cellular immunity processes.[9] These cytokines are mainly produced by Th2-lymphocytes, monocytes, macrophages, cytotoxic T-lymphocytes, and B-lymphocytes.[8],[9] Of these cytokines, IL-10 is the most important immunomodulatory and anti-inflammatory cytokine.[8],[10] It has two contradictory roles in the oncogenesis process; a tumor-promoting role and a tumor-inhibitory role.[8] The tumor-enhancing role of IL-10 is due to its immunosuppressive effects on macrophages and pro-inflammatory Th1-cells and also due to stimulation of the proliferation and differentiation of B-cells and Th2-cells and prevention of apoptosis, leading ultimately to cytotoxic response immunosuppression.[8],[11] On the contrary, the tumor-inhibitory action of IL-10 is primarily the result of the suppression of angiogenesis.[8]

According to some studies, IL-10 gene polymorphisms might play a part in the development of some malignant tumors, specifically lymphoid malignancies, including Non-Hodgkin lymphoma (NHL) and diffuse large B-cell lymphoma.[8],[9],[11] It has been linked with high bcl-2 expression in some B-lymphocyte malignancies.[9] Its relationship with CLL development is still under investigation.[8]

Another mutation that might have an effect on CLL prognosis is the splicing factor 3B subunit 1 (SF3B1) mutation. The SF3B1, which is situated on chromosome 2q33.1, is an important part of the splicing mechanism with a crucial role in RNA splicing.[4],[12],[13] This spliceosome machinery enhances introns removal from messenger RNA (mRNA).[12] The spliceosome is comprised small nuclear ribonucleoproteins (snRNPs) named U1, U2, U4, U5, and U6, in addition to several splicing factors.[12],[14] SF3B1 is an important element of the functional U2 snRNP that contains several proteins as a highly organized complex.[12],[15] It has an important role in detecting the branch point sequence and enhancing spliceosome assembly and activation.[15] Most SF3B1 mutations occur in its C-terminal domain that is composed of 22 HEAT repeats (Huntington, Elongation factor 3). Most of the mutations are present between the 5th and the 8th HEAT repeats.[12] Another location for SF3B1 mutations was identified at G742 of the SF3B1 gene in some CLL cases.[12] Some studies reported that about 18% of CLL new cases have SF3B1 mutation and suggested that it could be considered as a prognostic marker for CLL.[4],[12]

While some studies have linked SF3B1 mutations to a poorer prognosis of CLL, others demonstrated no significance in its prognostic value.[4],[16] Therefore, the SF3B1 mutation effect on CLL prognosis still requires further clarification.

From this context, we have great interest to investigate the effect of both IL-10 (1082G/A) gene polymorphism and SF3B1 (2098A/G) mutation on CLL in this study.

 Materials and Methods



Our study had been carried out in Alexandria Main University Hospitals on eighty CLL patients and eighty apparently normals of uniform age and sex as the control group. The study was conducted after the authorization of the Medical Ethics Committee of Alexandria Faculty of Medicine. The sample size was calculated using the G power version 3.1 statistical software program with a 0.05 level of significance and 80% power of the study. All study participants signed a written informed consent showing the nature and goal of the study in detail.

Diagnosis of CLL was made according to the WHO classification guideline.[17]

All CLL patients had undergone a complete blood count with the morphological examination, peripheral blood immunophenotyping for CLL markers (CD5, CD19, CD23) and molecular testing for both IL-10 Gene promoter Polymorphism (1082G/A) and SF3B1 polymorphism (2098A/G).

Nucleic acid extraction

Genomic DNA extraction was done from Ethylenediaminetetraacetic acid whole blood, adapting the protocol provided by the manufacturer using QIAamp DNA Blood Mini Extraction Kit (QIAGEN, USA). The amount and purity of the extracted nucleic acids were confirmed using Nanodrop 2000 spectrophotometer (NanoDrop Technologies). A 260/280 ratio of 1.7 up to 2.0 indicated high-quality DNA.

Interleukin-10 1082G/A genotyping

IL-10 promoter gene (1082G/A) SNP (rs1800896) was assessed by STRATAGENE real-time polymerase chain reaction (PCR) system using TaqMan platform (Applied Biosystems, USA). The PCR reaction mix included 12.5 uL Taqman Universal PCR mix, 0.5 uL Taqman SNP Genotyping Assay ×20, 2 uL extracted DNA, and DNase free water to a final volume of 20 uL. Two probes, one labeled with VIC to find the A allele and the other labeled with FAM to find the G allele, were used. Thermal cycling was done as follows: initial denaturation step at 95°C for 10 min followed by 35 cycles of denaturation at 95°C for 15 s and 1 min at 60°C for annealing and extension.

Splicing factor 3B subunit 1 2098A/G genotyping

The SF3B1 SNP polymorphism (2098A/G) (rs559063155) was assessed by STRATAGENE real-time PCR system using TaqMan platform (Applied Biosystems, USA). 1 uL of the working stock genotyping solution was added to 10 uL Taqman Universal PCR Master Mix with 2 uL of the extracted DNA. The reaction volume was 20 uL. Two probes, one labeled with VIC to find the A allele and the other labeled with FAM to find the G allele, were used. Thermal cycling was done as follows: Initial denaturation step at 95°C for 5 min followed by 35 cycles of denaturation at 95°C for 30 s, 30 s at 58°C for annealing, 30 s at 72°C for extension, and 7 min at 72°C for the final extension.

Statistical analysis

SPSS Statistics software, Version 22.0. Armonk, NY: IBM Corp. was used for statistical analysis of collected data. Chi-square test and Fisher's exact test were used to test categorical data. Quantitative data were presented as mean and standard deviation or median (minimum–maximum). Unpaired Student's t-test was used to compare between two groups of numerical normal distribution data. Mann–Whitney test was used to test for differences between the two groups. P < 0.05 were considered statistically significant.

 Results



Demographic and clinicopathologic data

The CLL patients group included 65 (81.3%) men and 15 (18.8%) women, with a mean age of 59.3 ± 8.2 years. The control group included 63 (78.8%) men and 17 (21.3%) women, with a mean age of 59 ± 6.8 years. There was no statistical significance between both groups in sex (P = 0.693) and age (P = 0.801). The characteristics of the study particpants are summarised in [Table 1].{Table 1}

Regarding lactate dehydrogenase (LDH) level, [Table 1] shows that the mean LDH level in CLL patients was 415 ± 299.5 U/L and the mean LDH level in the control group was 165.6 ± 44 demonstrating statistical significance (P < 0.001).

Similarly, [Table 1] also shows that hemoglobin level, white blood cells (WBC) count, and platelets count are statistically significant between the CLL patients and the controls (P < 0.001).

[Table 2] presents the clinicopathologic data of CLL patients. According to Rai classification, 37 patients (46.3%) were in low stage, 16 (20%) in the intermediate stage, and 27 (33.8%) were in high stage.{Table 2}

Interleukin-10 (1082G/A) genotyping

[Table 3] shows the genotype and allele frequencies of the proximal region of IL-10 promoter 1082G/A polymorphisms in the controls and the patients. The distribution of the analyzed genotypes was in conformity with the Hardy-Weinberg equilibrium in the controls and cases.{Table 3}

Among the patients group, 20% showed G/G genotype, 60% showed A/G genotype and 20% showed A/A genotype. Whereas among controls, 50% showed G/G genotype, 40% showed A/G genotype and 10% showed A/A genotype.

Overall, comparative analysis revealed that IL-10 (A/G) genotype, IL-10 (A/A) genotype and IL-10 A allele were significantly higher among CLL cases compared with controls (P < 0.001, 0.002 and <0.001 respectively). On the other hand, IL-10 (G/G) genotype and IL-10 G allele prevalence were statistically insignificant between both groups [Table 3].

Therefore, analysing the data using Odd's ratio revealed that the risk of developing CLL was significantly associated with IL-10 (A/G) genotype, IL-10 (A/A) genotype and IL-10 A allele, but was not proved to be associated with IL-10 (G/G) genotype and IL-10 G allele (OR=3.750, 95% CI: 1.803-7.799, p<0.001 for A/G, OR=5.000, 95% CI: 1.789-13.975, p=0.002 for A/A, OR=2.333, 95% CI: 1.475-3.691, P < 0.001 for A allele).

Meanwhile, [Table 4] shows that age, sex, hemoglobin level, WBC count, platelets, LDH, lymphocyte doubling time (LDT), Rai staging, survival, ZAP70, CD38, and clinical remission were statistically insignificant with all IL-10 genotypes.{Table 4}

[Table 5] shows that there was no significant difference in IL-10 alleles and genotypes among CLL patients according to disease stage.{Table 5}

SF3B1 (2098A/G) Genotyping

[Table 3] shows that SF3B1 mutation (A/G) was detected in 15 patients (18.8%) and in 3 controls (3.8%), indicating the presence of statistical significance between both groups (P = 0.007).

Among the patients group, 81.3% showed A/A genotype, 18.8% showed A/G genotype. Whereas among controls, 96.3% showed A/A genotype, 3.8% showed A/G genotype and 10% showed A/G genotype. No one showed SF3B1 G/G genotype among patients or controls.

Overall, comparative analysis revealed that SF3B1 (A/G) genotype and SF3B1 G allele were significantly higher among CLL cases compared with controls (P = 0.007 and P = 0.009 respectively). On the other hand, SF3B1 (A/A) genotype and SF3B1 A allele prevalence were statistically insignificant between both groups [Table 3].

Therefore, analysing the data using Odd's ratio revealed that the risk of developing CLL was significantly associated with SF3B1 (A/G) genotype and SF3B1 G allele, but was not proved to be associated with SF3B1 (A/A) genotype and SF3B1 A allele (OR=5.923, 95% CI: 1.642-21.363, P = 0.007 for A/G and OR=5.414, 95% CI: 1.536-19.085, P = 0.009 for G allele).

[Table 4] shows that age, sex, hemoglobin level, WBC count, platelets, LDH, LDT, Rai staging, survival, ZAP70, CD38, and clinical remission were statistically insignificant with the SF3B1 mutation except for organomegaly (P < 0.001).

[Table 6] shows that there was not any significant difference in the SF3B1 mutation frequency with regards to Rai disease classification.{Table 6}

 Discussion



IL-10 is an immunoregulatory cytokine that shows multifunctional effects on tumor cells. It stimulates the accumulation of some malignant B-lymphocyte cells and plays a suppressive role on the immune reaction against tumor cell proliferation. In addition, IL-10 has both stimulatory and suppressive functions on the T-lymphocytes.[18] Some studies suggested that IL-10 suppresses cancer cells by stimulating CD8+ T cells,[19],[20] whereas other researches revealed that IL-10 can lead to stimulation of tumor cell proliferation.[21],[22]

IL-10 SNPs have been involved in infectious diseases, autoimmunity, and cancers such as gastric cancer, breast cancer, cervical cancer, and prostatic malignancy.[9],[18]

Several studies have tested the relationship between polymorphism in the promoter region of IL-10 and the risk of different cancers, including leukemia, yet the results were conflicting. In our study, we found that IL-10 promoter-1082 G/A and A/A genotypes and the A alleles might be a risk factors for CLL development. Similarly, Ovsepyan et al. demonstrated that IL-10 promoter-1082 A/A are significantly linked with more advanced CLL stages than among those in the early stage.[8] They assumed in their research that this might be due to the appearance of aggressive clones of malignant cells due to defective suppression of new malignant cells or stimulation of their proliferation in the-1082 A/A genotype. Kowalska et al. studied monocytic myeloid-derived suppressor cells (M-MDSCs) with intracellular IL-10 in CLL patients by flow cytometry.[23] They found out that there was increased M-MDSCs producing IL-10 in CLL and that there was an association with immune response suppression in CLL and shorter time to treatment. In contrast to our current research, a recent metanalysis study showed that there was an association between-1082 G/G genotype of the IL-10 gene and the low risk of chronic leukemia, including CLL when compared to AA and G/A + A/A.[18] Although our results conflict with theirs, this could be due to the following factors. First, genetic variations among various populations, for example, the Chinese people, might not respond to the same polymorphism in the same way like the Egyptians, on whom we carried out our study. Second, IL-10 has both stimulatory and inhibitory roles on the different immune cells and how it is expressed is still under investigation. Finally, CLL, like all cancers, is a multifactorial disease with no specific cause; therefore, genetic susceptibility might play a role in the difference recognized between studies.

On another note, Ye et al. studied the link between-1082 IL-10 polymorphisms and other NHLs.[24] He found out that-1082 IL-10 polymorphism was significantly associated with NHL as a whole, B-cell lymphomas, and DLBCL in the Chinese people. Similarly, Lech-Maranda et al. demonstrated that high expression of-1082 G allele of IL-10 might be a risk factor for DLBCL and assumed that this may be due to stimulation of the B-cells and lymphoma cells proliferation by IL-10 polymorphism.[25]

In the current study, we also showed that SF3B1-2098A/G gene mutation might be linked to CLL occurrence. And this could be partially due to activation of the NOTCH1 pathway leading to reduction of CD20 gene expression.[26] Our study detected no significant association between SF3B1 gene mutation and the CLL disease stage.

Our results conformed with other studies that showed that SF3B1-2098A/G mutation is significantly related to CLL development but not staging.[3] In addition, they demonstrated that SF3B1 mutation is related to reduced overall survival. Quesada et al. and Wang et al. demonstrated that SF3B1-2098A/G gene mutation was significantly related to CLL development and poor prognosis[27],[28] and this was explained by Te Raa et al. in a previous study demonstrating that SF3B1 mutations are linked to high frequency of DNA damage and defective apoptotic responses to DNA damage.[29] Similarly, Leeksma et al. studied SF3B1 mutations and confirmed nonsense-mediated mRNA (NMD) being involved in the pathological actions of SF3B1 mutations, raising the possibility of that NMD modulatory agents could be of benefit to CLL patients with SF3B1 mutation.[30]

Landau et al. demonstrated that SF3B1 mutation-2098A/G is a later event in CLL progression and not only induces neoplastic B-cell proliferation but also drive a more aggressive course of the disease.[31] Other studies suggest that the explanation behind SF3B1 mutation being linked to CLL poor prognosis might be due to NOTCH1 pathway activation by the SF3B1 mutated CLL cells.[28],[32],[33] In addition, Thompson et al. and Rossi et al. showed that SF3B1-2098A/G mutation might lead to poor response to chemotherapy due to biological similarity of SF3B1 and NOTCH1 CLL mutations.[34],[35] Tang et al. used nanopore sequencing through the Full-Length Alternative Isoform analysis of RNA (FLAIR) to study cDNA samples from CLL patients with and without SF3B1 mutations and they found out that there were differential 3' splicing changes related to the SF3B1 mutation.[13] They recommended the nanopore and FLAIR technology to identify cancer-specific transcript variants as potential future prognostic biomarkers of the disease.

 Conclusion



Our results showed that IL-10 gene promoter region SNPs (1082 A/G and A/A) and A alleles might be associated with increased risk of CLL development compared with G/G genotypes and G alleles and are a probable risk factor for the disease. Furthermore, our study demonstrated that SF3B1-(2098A/G) SNP and G alleles mutations are related to and might be a causative factor for CLL.

Several limitations of our study should be mentioned, which are the relatively small sample size and the detection of the IL-10 and SF3B1 polymorphisms by reverse transcription-PCR only at the baseline level without follow-up after treatment. Therefore, we do recommend further studies to be carried out on larger sample size and with following-up the patients for a specific time period to detect any changes over time to confirm and validate our results. We do also recommend to use gene sequencing methodologies and include other immunologic genes to clarify the genetic risk factors for CLL more precisely.

Acknowledgments

The authors would like to thank all the patients and their families for participating in this project.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

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