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Full Research Article

Interplaying Correlation of Some Genetic and Inflammatory Factors among Patients with Polycythemia Vera

Yusra Ghiath1, Baan Abdulatif Mtashar2, Noor AL-Huda Salah AL-Zuhairy3, Mohanad Salam Hussein1, Ahmed Flayyih Hasan4,5,*
  • 0009-0007-9208-5046
1National Center of Hematology, Mustansiriyah University, Baghdad, Iraq.
2Department of Microbiology, Collage of Medicin, Mustansiriyah University, Baghdad, Iraq.
3Department of Pharmacology and Toxicology, College of Pharmacy, Mustansiriya University, Baghdad, Iraq.
4Biotechnology Research Center, Al-Nahrain University, Baghdad, Iraq.
5Department of Biology, Al-Farabi University College, Baghdad, Iraq.

ABSTRACT

Background: Polycythemia vera (PV) is a myeloproliferative neoplasm characterized by the overproduction of red blood cells. A key feature of PV is the dysregulation of cytokine networks, with elevated levels of various pro-inflammatory cytokines contributing to disease progression. The JAK2 mutation, a common genetic driver of PV, stimulates the production of these cytokines, leading to increased cell proliferation, inhibited apoptosis and inflammation. Estimation of IL-12 and IL-21 Level and study the correlation between of theses cytokine with JAK2 V617F and hematological parameters.

Methods: This study investigated 60 patients diagnosed with polycythemia vera (PV) at the National Center of Hematology between January 2023 and July 2024. The patient group consisted of 33 females and 27 males, with ages ranging from 18 to 75 years. Detection JAK2 V617F using Poly chain reaction (PCR) as well as estimation of IL-12 and IL-21 by sandwich ELISA technique.

Result: In this Study 31 of PV patients detected as JAK2 V 617F Negative while 29 patients were positive. Also, this study examined the role of IL-12 and IL-21 in polycythemia vera (PV). Patients with the JAK2 V617F mutation had significantly higher IL-12 levels, suggesting a strong association. However, no significant differences were found in IL-21 levels between groups. Additionally, WBC count and platelets count were positively correlated with IL-21.

INTRODUCTION

Polycythemia vera (PV) is a myeloproliferative neoplasm (MPN) characterized by hyperproliferation of erythroid progenitors. Mutation in the JAK2 gene is a common genetic driver of PV, leading to constitutive activation of downstream signaling pathways. The clinical manifestations of PV include thrombotic complications, symptoms associated with increased blood viscosity, disease progression to secondary myelofibrosis or acute leukemia (Barbui et al., 2023: Tefferi et al., 2021). The incidence rate of PV is higher in women than men, with a rate of o.68-2.6 cases per 100000 people per year. PV is uncommon people younger than 60 and the average life expectancy after diagnosis is 14 years (Cacemiro et al., 2020: Spivak et al., 2014).PV is considered an onco-inflammatory disease bec ause PV patients exhibit augmented levels of several pro-inflammatory cytokines (Cacemiro et al., 2020).he bones marrow microenvironment serves as a milieu to produce cytokines and growth factors, which significantly impact the regulation of cellular survival, proliferation, differentiation and immune responses (Jahandideh et al., 2020; Abass et al., 2025). The understanding of cytokine function has not only led to the development of supportive therapies, such as Erythropoietin (EPO), but also plays a crucial role in the diagnosis of certain hematopoietic disorders. For instance, the subnormal serum EPO level is one of the minor criteria for polycythemia vera (PV) according to the WHO 2008 classification. This suggests that the dysregulation of cytokines can be a valuable biomarker in the identification of these disorders (Vardiman et al., 2010). Elevated levels of inflammatory cytokines have been reported in all entities of classical MPN and could be consider as prognostic factor for survival patient IL-8, IL-2R, IL-12 and IL-15 (Tefferi et al., 2011: Vaidya et al., 2012).

Furthermore, cytokine levels in myelofibrosis have been shown to predict response to treatment with pomalidomide (Pourcelot et al., 2014: Pardanani et al., 2011) and JAK inhibitor therapy-induced down regulation of pro-inflammatory cytokines has been correlated with response in constitutional symptoms (Rentschler et al., 2022: Verstovsek et al., 2010). Number of cytokines have been studied in patients with myeloproliferative neoplasms (MPNs). Among these, several have shown potential connections to the progression of all types of MPN or have been linked to prognosis. These include IL-1β, TNF-α, IL-6, IL-8, VEGF, PDGF, IFNs and TGF-β. While other cytokines like IL-1α, IL-2Ra, IL-11 and MIP-1 have been investigated, their role in MF progression or prognosis is less clear (Wang et al., 2019). The equilibrium between pro-inflammatory and anti-inflammatory cytokine effects is crucial for  maintaining no rmal physiological functions. Imbalances can le ad to organdys function or diseases. In the context of myelopro liferative neoplasms (MPN), abnorm alities in cytokine networks have been documented, highlighting their critical role in disease pathology  (Hoermann  et al., 2015). In polycythemia vera,  there is an  observed  elevation in  various cytokines, including IL-1β, IL-1RA, IL-2, IL-2R, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12, IL-13,  IL-15, IL17, EGF,etoxin, FGF-b, GM-CSF, IFNγ,  MCP1,  PDGF-BB, TNFα, VEGF, HGF and erythropoietin (EPO ). This complex cytokine profile under scores the intricate network of immune responses involved in the patho  physiology of the disease (Holdsworth et al., 2015). JAK2-mutated hematopoietic progenitor and stem cells (HPSCs) secrete IL1β, TNFα, IL-12 and IFNγ, among other proinflammatory cytokines, which provide a survival advantage to the mutated HPSCs and serve as promoters of mutagenesis (Waksal  et al., 2024). Understanding the role of cytokine network dys regulation in PV is essential for developing effective therapeutic strategies. Targeting specific cytokines or their signaling pathways may offer promising avenues for treating these complex disorders.

MATERIALS AND METHODS

Subjects
 
Sixty myeloproliferative (MP) patients diagn osed  with polycythemia vera (PV)  were clinically  and laboratory diag nosed at the National Centre of Hematology, Mustansiriyiah University, between January 2023  and July 2024. Among these patients, 33 were female and 27 were male, with ages ranging from 18 to 75 years. The diagnosis was based on the 2008 World Health Organ ization classification Vardiman et al., (2009). Additionally, 30 healthy individuals served as the control group. This study designed as case control.

Inclusion criteria
 
Patients diagnosed with PV, age between 18 to 75, JAK2V617F positive and Negative.
 
Exclusion criteria
 
Other MPN patients, Age under 18 and pregnant women.
 
Sample collection
 
Peripheral blood samples from each patient and control group were collected by venipuncture using a disposable 10 ml syringe and it was drawn into two tubes, one of EDTA tubes for CBC, Blood picture and DNA extraction and other of plan tubes which subjected to centrifugation (2000 rpm for 15 minutes) to collect sera that were employed in IL-12, IL- 21 and EPO  assessments.
 
DNA Extraction
 
EDTA blood sample was used to extract genomic DNA according to the manufacturer’s instruction of Promega Corporation / USA; by using wizard genomic DNA purification kit.
 
Polymerase chain reaction (PCR)
 
To detect the JAK2 V617F (499 pb) mutation, DNA was amplified in exon 14 by using ARMS-PCR technique (Table 1 and 2).

Table 1: The JAK2 V617F primers sequences (IDT, Korea).



​

Table 2: Thermal cycler condition for PCR amplification to detection JAK2 V617F using thermal cycler ( Bio-Rad C1000 , USA).


 
Assessment of IL-12, IL-21 and EPO
 
The level of IL-12 and EPO  (RandD / USA) and IL-21 (Elabscience/China)  were determined by an enzyme-linked immunosorbent assay (ELISA). The principal method was Sandwich ELISA and the concentrations of Cytokines were determined with a standard curve derived from known amounts of the relevant cytokine using absorbance readings at 450 nm on a spectrophotometer (ELISA reader) (Mindray /China) .
 
Statistical analysis
 
The statistical analysis was conducted using the software package SPSS IBM Corp., Released 2021. IBM SPSS Statistics for Windows, Version 26.0. (IBM Corp., Armonk, NY). Demographic data were characterized using descriptive statistics, mean, percentage, ratio and T-test. Estimated p-values<0.05 were considered significant.

RESULTS AND DISCUSSION

Finally, the amplified PCR products were to electrophoresis using 1% agarose gel with red safe (0.5 µg/ml) (Promega /USA) for 30 minutes (10 Volts/cm2) using gel electrophoresis instrument (Media/ korea). A100 bp DNA ladder (Promega /USA) was employed to assess the PCR product size. The products were Visualized under UV light at 336 nm using UV documentation (Germany).
       
This study is conducted on 60 patients with PV, after detection of JAK2 V617 F mutation, 31 (51.67%) patients of them were negative JAK2 617F, while the rest 29 (48.33%) patients were positive Fig 1, along with those patients, 30 healthy looking persons are enrolled to act as control group with matched age and gender. The age mean showed non-significant differences between control group (51±14 year) and patients (50.42±313.4). Also, female to male ratio in PV patients is 1.22, thus the distribution of female to male ratio in control group (1.3) is conducted to be matched with that in patients and with non-significant difference Table 3.

Fig 1: Detection of the JAK2V617F mutation in peripheral blood of polycythemia vera.



​

Table 3: Baseline characteristic of study groups.


 
Estimation levels of IL-12 , IL-21 and EPO
 
In this study comparing the level of IL-12 and IL-21 between control and JAK2 V617F positive and negative groups, significant differences were found. The control group (n=30) had IL-12 levels of 92.9±12.6, while the positive group (N=29) and negative group (N=31) had markedly higher level 262±109.1 and 266±135.9 respectively, with p-value <0.001. Similarly, IL-21 level were 329.4±56.9 in the control group, 348.5±128.9 in the positive group and 413±176.4 in the negative group, also with p-value 0.116. These findings suggest a strong correlation between JAK2 V617F mutation and increased IL-12 while no correlation with IL-21 levels. The EPO levels are significantly lower in the JAK2 V617F-positive group (2.7±1.20) compared to both the JAK2 V617F-negative group (19.8±7.56) and the control group (10.8± 2.8). This difference is statistically significant with a p-value of less than 0.001.
       
In summary, the JAK2 V617F-positive group exhibits significantly lower EPO levels than the other two groups. Table 4.

​

Table 4: Comparison of IL-12, IL-21 and EPO levels among control, JAK2 V617F-Positive and JAK2 V617F-Negative Groups.


       
The study included 60 participants, 31 of whom were negative for the JAK2 V617F mutation. Among the 29 positive individuals, IL-12 levels were found to be 266.3±135.9, also IL-21 levels were non significantly differences at 348.5±128.9 compared to the negative group (262.1±109.1 and 413±176.4, respectively). The p-value for IL-12 and IL-21 was 0.897, 0.145 respectively, indicating no significant difference. The level of EPO shows significant differences between JAK2 V617F positive and Negative groups (p<0.001) (Table 5).

​

Table 5: Comparison of IL-12 , IL-21 and EPO levels between JAK2 V617F-Positive and JAK2 V617F-Negative Groups.


       
In comparison the levels of IL-12, IL-21 and EPO between a treated group (n=23) and an untreated group (n=37). The mean IL-12 level in the treated group was 290±123.2, while in the untreated group it was 250.5±121.4. This difference was not statistically significant (p=0.23). The mean IL-21 level in the treated group was 367.6±123.6 and in the untreated group it was 387.2±178.4. This difference was also not statistically significant (p=0.06). In order to EPO, the mean EPO level in the treated group was 12.7±8.72 and in the untreated group it was 10.6±9.71. This difference was also not statistically significant (p=0.459) (Table 6).

​

Table 6: Comparison of IL-12, IL-21 and EPO Levels between treated and untraded groups.


       
The study examined the relationship between blood parameters (WBC, HB, HCT and platelets) and the cytokines IL-12 and IL-21. While WBC levels were weakly positively correlated with IL-12 (r = 0.346, p = 0.640), they were significantly positively correlated with IL-21 (r = 0.289, p = 0.026). Hemoglobin and hematocrit levels showed no significant associations with either cytokine. Interestingly, platelet levels were positively correlated with IL-21 (r = 0.813, p = 0.001) but not with IL-12 (r = 0.085, p = 0.522). The cytokines themselves, IL-12 and IL-21, were not significantly correlated (r = 0.119, p = 0.368). The correlation between EPO and WBC is not statistically significant (r = 0.247, p = 0.059), while the correlation between EPO and HB is statistically highly significant correlation ( (r = 0.34, p = 0.008). Also the correlation between EPO and HCT and Platelets are statistically significant correlation (r = 0.281, p = 0.031; r = 0.320, p = 0.014). Finally there were no statistically significant correlation among EPO, IL12 and IL21 , (Table 7).

​

Table 7: Relationship among study parameters.


       
JAK2 V617F is associated with clonal hematopoiesis, genomic variation, dysfunction in hemostasis and immune response. JAK2 V617F Variant is a high frequency in PV, leading to constitutive activation of the JAK-STAT signaling pathway and increased proliferation of hematopoietic cells (hasan et al., 2024; Hameed et al., 2024; Alyasiri et al., 2024). Several studies have reported elevated levels of various cytokines, including IL-6, IL1-2, IL-17, IL-18, VEGF, TNF-α and TGF-β, in PV patients. These cytokines may contribute to the development of thrombotic complications and disease progression (Patterson et al., 2023).IL-12 and IL-21: These cytokines play important roles in immune regulation and inflammation. IL-12 is a potent inducer of Th1 cell differentiation and IFN-γ production (Ullrich et al., 2020; Yahya et al., 2024). while IL-21 is involved in B-cell and T-cell activation (Biewenga et al., 2022). The findings of this study provide valuable insights into the complex interplay between genetic factors, cytokine dysregulation and clinical manifestations in PV. The increased IL-12 levels in both JAK2 V617F-positive and negative patients suggest that this cytokine may play a broader role in the pathogenesis of PV than previously recognized. Previous studies illustrated that IL-12 are potential biomarker of onco-inflammatory cytokine and may contributes to disease development and progression (Jain et al., 2021: Cattaneo et al., 2021 ; Al-Maliki  et al., 2024). The lack of a significant association between IL-21 levels and JAK2 V617F mutation status suggests that IL-21 may not be a primary driver of PV pathogenesis. However, the positive correlation between platelet count and IL-21, gene profiling studies have indicated that in vitro differentiated human megakaryocytes express the receptor for IL-21 (IL-21R), an immunostimulatory cytokine associated with inflammatory disorders and currently under evaluation in cancer therapy. It is possible that IL-21 may have a role in regulating megakaryopoiesis or platelet function (Pesce et al., 2020: Behrens et al., 2018). In current study the level of EPO in JAK2 V617F positive group lower than JAK2 617F Negative group with significant result (p<0.001). Cells carrying the JAK2 V617F mutation exhibit increased sensitivity to erythropoietin (EPO), a hormone that stimulates red blood cell production (Benbarche et al., 2017: Dupont et al., 2007).In some cases, cells with the JAK2 V617F mutation can become independent of EPO, meaning they can proliferate and differentiate into red blood cells even in the absence of EPO. This further contributes to the overproduction of red blood cells in PV patients. This heightened sensitivity leads to excessive red blood cell production (Lanikova et al., 2016). As a result of the increased red blood cell mass and the autonomous proliferation of erythroid cells, the body’s demand for EPO decreases. This leads to lower serum EPO levels in PV patients, which can be used as a diagnostic marker for the disease (Yoon et al., 2024). The lack of a significant impact of treatment on cytokine levels suggests that current therapies may not effectively target the underlying inflammatory processes in PV. Future studies should explore novel therapeutic strategies aimed at modulating cytokine production or signaling pathways to improve clinical outcomes. Targeting cytokine signaling pathways may offer a novel therapeutic approach for PV. For example, JAK inhibitors, such as ruxolitinib, have shown efficacy in reducing disease burden and improving clinical outcomes in PV patients (Verstovsek et al., 2012: Braun et al., 2010).

CONCLUSION

This study provides indication for the involvement of IL-12 in the pathogenesis of polycythemia vera, regardless of JAK2 V617F mutation status. Further research is needed to elucidate the accurate mechanisms by which IL-12 promotes disease development and progression. Additionally,  the potential role of IL-21 in regulating platelet function permits further investigation. The lower EPO levels in JAK2 V617F-positive patients are consistent with the known mechanisms of JAK2 V617F-mediated EPO hypersensitivity and independence. The lack of significant impact of treatment on cytokine levels highlights the need for novel therapeutic strategies that target underlying inflammatory processes.

CONFLICT OF INTEREST

All authors declared that there is no conflict of interest.

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