Dysregulation of MicroRNA-181a-5p Targets TNFAIP3 to Promote MIF-CXCR4 Signaling and Immune Inflammatory Remodeling in Chronic Myeloid Leukemia

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Methods The study included 57 individuals with chronic myeloid leukemia (CML) and 33 healthy individuals. Hematological parameters (Hb, RBCs, WBCs and platelets) were assessed. The serum levels of MIF, TNFAIP3 and CXCR4 were measured using ELISA Technique. Quantitative real-time polymerase chain reaction was performed to assess miR-181a expression. The potential targets and immune associated pathways of miR-181a were predicted using bioinformatics tools including TargetScan, miRTarBase, STRING, DAVID, and Enrichr. Statistical analysis included ROC curve evaluation, Pearson correlation, and t-tests. Results Compared to controls, CML patients exhibited reduced platelets, Hb and RBC while elevated WBCs recorded. There were significantly elevated serum levels of MIF and CXCR4, and reduced levels of TNFAIP3 (p<0.01) in CML patients compared to control. Moreover, higher miR-181a expression (2.28 fold, p=0.0001) recorded in CML compared to control. Positive correlations were observed between miR-181a expression and both MIF and CXCR4 levels while TNFAIP3 exhibited a reverse correlation. ROC analysis showed that MIF (AUC = 0.873) and CXCR4 (AUC = 0.929) exhibited strong diagnostic performance while TNFAIP3 (AUC = 0.142) and miR-181a-5p (AUC = 0.201) demonstrated weak accuracy consistent with their opposite expression patterns between CML patients and healthy controls. Conclusion The inhibition of TNFAIP3 by miR-181a leads to enhanced NF-κB-mediated inflammatory and immune signaling suggesting a novel pathogenic mechanism in CML involving immune dysregulation. The identification of miR-181a, MIFpresent3, and CXCR4 as key players in immune modulation and inflammation presents promising therapeutic targets and diagnostic biomarkers in CML particularly within the Iraqi population. 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F1000Research 2025, 14 :1460 ( https://doi.org/10.12688/f1000research.172236.1 ) NOTE: If applicable, it is important to ensure the information in square brackets after the title is included in all citations of this article. Close Copy Citation Details Export Export Citation Sciwheel EndNote Ref. Manager Bibtex ProCite Sente EXPORT Select a format first Track Share ▬ ✚ Research Article Dysregulation of MicroRNA-181a-5p Targets TNFAIP3 to Promote MIF-CXCR4 Signaling and Immune Inflammatory Remodeling in Chronic Myeloid Leukemia [version 1; peer review: 2 approved with reservations] Noha Mohammed Saleh https://orcid.org/0000-0002-3957-7304 1 , Rawaa AlChalabi 2 , Yasir Issa 3 , Shahad Nassurat 4 Noha Mohammed Saleh https://orcid.org/0000-0002-3957-7304 1 , Rawaa AlChalabi 2 , Yasir Issa 3 , Shahad Nassurat 4 PUBLISHED 26 Dec 2025 Author details Author details 1 Pathology, Al Iraqia University College of Medicine, baghdad, 3, 10079, Iraq 2 Department of Molecular and Medical Biotechnology, College of Biotechnology, Al-Nahrain University, baghdad, 3, 10079, Iraq 3 College of Health and Medical Techniques/ Baghdad, Middle Technical University, baghdad, 3, 10079, Iraq 4 Biology, Middle East University, baghdad, 3, 10079, Iraq Noha Mohammed Saleh Roles: Data Curation, Funding Acquisition, Methodology, Project Administration Rawaa AlChalabi Roles: Project Administration, Resources, Supervision, Visualization, Writing – Review & Editing Yasir Issa Roles: Formal Analysis, Writing – Original Draft Preparation, Writing – Review & Editing Shahad Nassurat Roles: Funding Acquisition, Investigation OPEN PEER REVIEW DETAILS REVIEWER STATUS This article is included in the Fallujah Multidisciplinary Science and Innovation gateway. Abstract Background The non-coding RNAs, particularly microRNA-181a-5p target the expression of tumor necrosis factor alpha-induced protein 3 (TNFAIP3) a key negative regulator of NF-κB signaling and affect the levels of macrophage migration inhibitory factor (MIF) and chemokine receptor type 4 (CXCR4) in chronic myeloid leukamia (CML). Methods The study included 57 individuals with chronic myeloid leukemia (CML) and 33 healthy individuals. Hematological parameters (Hb, RBCs, WBCs and platelets) were assessed. The serum levels of MIF, TNFAIP3 and CXCR4 were measured using ELISA Technique. Quantitative real-time polymerase chain reaction was performed to assess miR-181a expression. The potential targets and immune associated pathways of miR-181a were predicted using bioinformatics tools including TargetScan, miRTarBase, STRING, DAVID, and Enrichr. Statistical analysis included ROC curve evaluation, Pearson correlation, and t-tests. Results Compared to controls, CML patients exhibited reduced platelets, Hb and RBC while elevated WBCs recorded. There were significantly elevated serum levels of MIF and CXCR4, and reduced levels of TNFAIP3 (p<0.01) in CML patients compared to control. Moreover, higher miR-181a expression (2.28 fold, p=0.0001) recorded in CML compared to control. Positive correlations were observed between miR-181a expression and both MIF and CXCR4 levels while TNFAIP3 exhibited a reverse correlation. ROC analysis showed that MIF (AUC = 0.873) and CXCR4 (AUC = 0.929) exhibited strong diagnostic performance while TNFAIP3 (AUC = 0.142) and miR-181a-5p (AUC = 0.201) demonstrated weak accuracy consistent with their opposite expression patterns between CML patients and healthy controls. Conclusion The inhibition of TNFAIP3 by miR-181a leads to enhanced NF-κB-mediated inflammatory and immune signaling suggesting a novel pathogenic mechanism in CML involving immune dysregulation. The identification of miR-181a, MIFpresent3, and CXCR4 as key players in immune modulation and inflammation presents promising therapeutic targets and diagnostic biomarkers in CML particularly within the Iraqi population. READ ALL READ LESS Keywords Chronic myeloid leukemia, CXCR4, Immune biomarkers, Inflammation, MIF, miR-181a, NF-κB signaling, TNFAIP3. Corresponding Author(s) Yasir Issa ( [email protected] ) Close Corresponding author: Yasir Issa Competing interests: No competing interests were disclosed. Grant information: The author(s) declared that no grants were involved in supporting this work. Copyright: © 2025 Mohammed Saleh N et al . This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The author(s) is/are employees of the US Government and therefore domestic copyright protection in USA does not apply to this work. The work may be protected under the copyright laws of other jurisdictions when used in those jurisdictions. How to cite: Mohammed Saleh N, AlChalabi R, Issa Y and Nassurat S. Dysregulation of MicroRNA-181a-5p Targets TNFAIP3 to Promote MIF-CXCR4 Signaling and Immune Inflammatory Remodeling in Chronic Myeloid Leukemia [version 1; peer review: 2 approved with reservations] . F1000Research 2025, 14 :1460 ( https://doi.org/10.12688/f1000research.172236.1 ) First published: 26 Dec 2025, 14 :1460 ( https://doi.org/10.12688/f1000research.172236.1 ) Latest published: 26 Mar 2026, 14 :1460 ( https://doi.org/10.12688/f1000research.172236.3 )  There is a newer version of this article available. Suppress this message for one day. Introduction The Philadelphia chromosome, a key component of chronic myeloid leukemia (CML), activates signaling pathways like RAS/MAPK, PI3K/AKT, and JAK/STAT, promoting cell proliferation and suppressing apoptosis. 1 , 2 Tyrosine kinase inhibitors (TKIs) have greatly enhanced the outlook for CML patients, leading to long-lasting remissions and a considerable increase in survival rates. 3 Research suggests that microRNAs (miRNAs) and other non-coding RNAs play a role in CML oncogenesis, stemness, and treatment resistance control. MicroRNAs, which are regulatory RNAs with a tiny size (about 22 nucleotides),fix to matching sequences in the 3 prim untranslated region (UTR) or coding sections of messenger RNAs (mRNAs) and suppress gene expression by mRNA degradation or translational inhibition. 4 MiR-181a affects cell survival and proliferation by targeting oncogenic regulators. Certain miRNA signatures have been linked to resistance to TKIs, stem cell maintenance, and leukemic transformation, and dysregulation of miRNA networks has been noted across different phases of CML progression. 5 , 6 Due to its dual involvement in influencing apoptosis and immunological signaling, miR-181a has garnered significant attention among the miRNAs implicated in hematological malignancies. CML stem/progenitor cells downregulate miR-181a expression making them more susceptible to apoptosis and TKIs. Leukemic cell survival, immune evasion, and inflammatory responses are all regulated by the NF-κB signaling system. 7 In CML, the promotion of an inflammatory milieu and the survival of leukemic stem cells are caused by abnormal NF-κB activation, which improves the disease duration. 8 , 9 an essential negative regulator of the NF-κB pathway is TNFAIP3 (tumor necrosis factor alpha induced protein 3), or A20 which limits inflammation and apoptosis resistance. 10 The production of inflammatory mediators can be increased when TNFAIP3 expression is either lost or suppressed, as this can augment NF-κB activity. The NF-κB pathway includes MIF (macrophage migration inhibitory factor) and CXCR4 (C-X-C chemokine receptor type 4), two downstream targets that may promote the migration of leukemic cells, the remodeling of the microenvironment, and resistance to treatment. 11 While CXCR4 facilitates the chemotactic migration of leukemic cells to protect bone marrow niches, MIF is a pro-inflammatory cytokine that promotes tumor growth and immune evasion. In hematologic malignancies, upregulation of MIF and CXCR4 has been linked to a worse prognosis and treatment failure. 12 Few studies have explored the role of miR-181a and other non-coding RNAs in the context of CML research in Iraq. 13 Due to the genetic diversity in Iraq and the increasing number of hematologic malignancies including CML further local research into miRNA-mediated regulation mechanisms is required. Aims of the study The objective of this research was to compare the miR-181a expression levels and blood concentrations of MIF, TNFAIP3, and CXCR4 in CML patients with those in healthy controls. The study also aimed to use bioinformatics analysis to determine the downstream impacts on pathways mediated by NF-κB and the regulatory link between miR-181a and TNFAIP3. Materials and methods Study design This case-control experimental study was designed to compare the gene expression of miR-181a and the serum concentrations of selected biomarkers (MIF, TNFAIP3, CXCR4) between CML patients and healthy controls. Bioinformatics analysis was additionally performed to investigate molecular interactions between miR-181a and its target genes. Ethical approval The study protocol was approved by the Iraqi Ministry of Health/Medical City/Center of Hematology, Baghdad, Iraq (approval number 41008, dated 14-11-2024). Informed written consent was obtained from all participants. The study was carried out from November 2024 to November 2025. Sample size and subjects The study included 90 people: 33 healthy controls who were the same age and sex as the participants and 57 patients with chronic-phase CML. Hematology clinics and hospitals in Iraq’s capital city of Baghdad were the sites of participant recruitment. Inclusion and exclusion criteria Participants were to be adults aged >20 years who had recently been diagnosed with chronic-phase CML according to molecular, hematological, and clinical criteria. None of the health controls had a family history of autoimmune diseases, chronic inflammatory illnesses, or hematologic malignancies were included in this study. Patients with CML in its rapid or blast crisis phases, individuals using immunosuppressive medication, or those suffering from autoimmune or infectious disorders at the same time were excluded in this study. Hematological parameters Using the ADVIA 2120i Hematology Analyzer (Siemens Healthcare Diagnostics, Germany) at the Research Unit, College of Health and Medical Techniques/Baghdad, Middle Technical University, we immediately after blood collection measured complete blood counts (CBC), which include Hb, RBCs, WBCs, and PLTs. Serum biomarker measurement Enzyme-linked immunosorbent assay (ELISA) kits (Sunglong Biotech Co., China) were used to quantify the serum concentrations of TNFAIP3, MIF, and CXCR4. RNA extraction Following the manufacturer’s instructions, 500 μL of serum samples were treated with TRIzolTM Reagent (Thermo Scientific, USA) to extract total RNA, which includes short RNAs. The RNA pellet was rinsed with 70% ethanol and resuspended in nuclease-free water after being separated with chloroform and isopropanol for RNA precipitation. In order to determine the amount and quality of the RNA, a Quantus Fluorometer (Promega, USA) was used. cDNA synthesis Complementary DNA (cDNA) was produced from RNA extraction by means of the GoScriptTM Reverse Transcription System (Promega, USA). Reverse transcription with random primers and the GoScript enzyme was carried out at 42°C for 60 minutes after the RNA and primer were denaturated at 70°C for 5 minutes. The enzyme was then inactivated at 70°C for 15 minutes to complete the operation. Primers used in this study The sequences for miR-181a and RNU43 were obtained from the iRbase database ( https://www.mirbase.org/ ) and primers were designed consequently. The following primers were manufactured by Macrogen (Korea) and used in the study: miR-181a Forward Primer (miR-181a-F2): 5′-TGTTTGACCATCGACCGTTG-3′. miR-181a Reverse Transcription Primer (miR-181a-RT): 5′-GTTGGCTCTGGTGCAGGGTCCGAGGTATTCGCACCAGAGCCAACGGTACA-3′. RNU43 Reverse Transcription Primer (RNU43-RT): 5′-GTTGGCTCTGGTGCAGGGTCCGAGGTA TTCGCACCAGAGCCAACAATCAG-3′. RNU43 Forward Primer (RNU43-F): 5′-GTGAACTTATTGACGGGCG-3′. Universal Reverse Primer: 5′-GTGCAGGGTCCGAGGT-3′. The optimal annealing temperature was 55°C for each set of primers. To make working solutions, the concentration of primers was 10 pmol/μL, and the stock concentration was 100 pmol/μL, both of which were adjusted in nuclease free water. Gene expression quantification (Real-Time PCR) The relative expression of miR-181a was measured via qRT-PCR on a Mic qPCR Cycler (Bio Molecular Systems, Australia) with the GoTaq qPCR Master Mix (Promega, USA). A cDNA template, specific primers, and SYBR Green master mix were all components of each 20 μL PCR reaction. Initial denaturation was done at 95°C for 5 minutes, followed by 40-cycles of 95°C for 20 seconds, 55°C for 20 seconds (fluorescence collection), and 72°C for 20 seconds as the thermal cycling conditions. The relative expression was determined using the 2^-ΔΔCt method, also known as the Livac method, after normalizing the expression levels against the house keeping gene RNU43. Bioinformatics analysis Bioinformatics was used to predict the miR-181a-TNFAIP3 interaction utilizing the miRTarBase and TargetScan databases. Utilizing the STRING database, protein-protein interaction networks incorporating TNFAIP3, MIF, and CXCR4 were generated. The DAVID and Enrichr platforms were used to perform functional enrichment analysis on biological processes and signaling pathways. Statistical analysis The SPSS software (version 27) was used for all statistical analyses. An independent samples t-test was used to examine the differences between the control group and the CML patients. The correlation analysis was used to investigate the association between miR-181a expression and serum biomarker values. To evaluate the diagnostic adequacy of miR-181a and the investigated biomarkers, ROC curve analysis was carried out. Statistical significance was established when the p-value was less than 0.05. The relative gene expression of the target genes was assessed using the Livak (2^−ΔΔCt) method. 13 Results Demographic characteristics of the study population There was no significant difference in the age and sex distributions between the control. Percentages were derived from group totals (CML n = 57: 28 males, 29 females; Control n = 33: 16 males, 17 females). The sex distribution therefore corresponds to 49.1% male/50.9% female in CML and 48.5% male/51.5% female in controls (pairs sum to 100%). A chi-square test for the sex and age variable showed no difference across groups in sex distribution. For age (4 categories), the omnibus test showed χ 2 = 0.280, df = 3, p = 0.964 (NS) and demonstrated no disparity in age distributions, as indicated in Table 1 (p > 0.05). Table 1. The demographic characteristics of CML and control. Group Sex CML patients Control Chi-square P-value Sex Male 28 (49.1%) 16 (48.5%) 0.112 0.821 NS Female 29 (50.9%) 17 (51.5%) 0.043 0.932 NS Age (Years) 20-30 2 (3.5%) 1 (3.0%) 0.536 0.91 NS 30-40 11 (19.3%) 6 (18.2%) 0.633 0.892 NS 40-50 28 (49.1%) 15 (45.5%) 1.231 0.724 NS >50 16 (28.1%) 11 (33.3%) 1.000 1.00 NS Profile of study participants Table 2 showed that there were statistically significant changes in major hematological parameters between healthy controls and CML patients. The CML group had significantly lower hemoglobin levels (8.74 ± 0.20 g/dL) when compared to the control group (11.41 ± 0.48 g/dL; p = 0.0000). Patients had significantly reduced RBC counts (3.51 ± 0.04 ×10 6 /μL) compared to controls (4.69 ± 0.12 ×10 6 /Μl, p = 0.0000). Compared to the controls, the CML group had significantly higher WBCs counts (27.87 ± 0.77 ×10 3 /μL) with a p-value of 0.0000. In comparison to the controls, patients had significantly decreased platelet counts (174.69 ± 2.49 ×10 3 /μL) with a p-value of 0.0001. Chronic myeloid leukemia is characterized by severe hematologic dysregulation, as shown in Table 2 . Table 2. Hematological profile in CML compared to control. Parameter CML patients (Mean ± SE) Controls (Mean ± SE) P-value Hb 8.74 ± 0.20 11.41 ± 0.48 0.0000 ** RBC 3.51 ± 0.04 4.69 ± 0.12 0.0000 ** WBC 27.87 ± 0.77 14.96 ± 1.76 0.0000 ** Platelets 174.69 ± 2.49 226.25 ± 10.97 0.0001 ** ** Significant differences, p < 0.01. Biomarker expression Comparing CML patients with healthy controls using quantitative analysis of circulating biomarkers showed striking differences. Signifying increased macrophage activation, MIF levels were significantly higher in the CML group (172.73 ± 8.22 pg/mL) in comparison to the controls (102.25 ± 3.88 pg/mL; p = 0.0000). The TNFAIP3 levels were considerably lower in CML patients (231.91 ± 4.85 pg/mL) compared to controls (409.89 ± 11.54 pg/mL; p = 0.0000), which may indicate that the anti-inflammatory regulation through the NF-κB pathway was suppressed. Patients had significantly increased CXCR4 expression (125.06 ± 5.05 pg/mL) compared to controls (63.30 ± 3.49 pg/mL; p = 0.0000) suggesting that there was an increase in chemokine receptor signaling and potential leukemic cell movement. The inflammatory and immunological dysregulation linked to CML pathogenesis is highlighted by these biomarker profiles, as shown in Figure 1 . Figure 1. Serum levels of inflammatory and signaling biomarkers in CML patients and healthy controls. (A) MIF, (B) TNFAIP3, and (C) CXCR4 in CML patients (red bars) versus control subjects (blue bars). (p < 0.01, **). Relative expression of miR-181 in CML patients and control Patients with chronic myeloid leukemia (CML) had significantly higher transcript levels of miR-181 (2.28) than healthy controls fold change (1) according to relative quantification analysis (p = 0.0001) reported in Table 3 . Table 3. Gene expression of miR-181 in CML patients and controls. Group RNU43 CT (Mean ± SD) miR-181 CT (Mean ± SD) ΔCT (Mean ± SD) ΔΔCT (Mean ± SD) 2^-ΔΔCT (Mean ± SD) Fold change Control 15.83 ± 2.10 15.21 ± 1.78 -0.62 ± 1.35 0.00 ± 0.00 1.00 ± 0.00 1 CML 14.91 ± 1.98 13.10 ± 1.55 -1.81 ± 1.22 -1.19 ± 0.45 2.28 ± 0.51 2.28 P-value 0.0912 NS 0.061 NS 0.023 * 0.0001 ** 0.0001 ** – * p < 0.05. ** p < 0.01. Correlation between miR-181 expression and biomarkers In the study population, the Pearson correlation analysis showed a slight association between the miR-181-fold change and the levels of MIF (r = 0.617, p < 0.0001) and CXCR4 (r = 0.630, p < 0.0001). The expression of miR-181 was shown to be strongly correlated negatively with TNFAIP3 levels (r = -0.758, p < 0.0001). Based on these results it appears that CML-specific inflammatory and chemokine signaling patterns are linked to miR-181 expression. As reported in Table 4 . Table 4. Correlation between miR-181-fold change and serum biomarker levels. Biomarker Correlation with miR-181 (r) P-value MIF 0.617 0.0000 ** TNFAIP3 -0.758 0.0000 ** CXCR4 0.630 0.0000 ** ** p < 0.001. Diagnostic performance of biomarkers and miR-181 In CML patients, ROC analysis showed that the sensitivity, specificity, AUC, cutoff, and p-value for MIF were 80.6%, 100.0%, 0.873, 80.10 pg/mL and p<0.001, respectively; for CXCR4 were 81.9%, 100.0%, 0.929, 68.10 pg/mL, and p<0.001, respectively; for TNFAIP3 were 6.9%, 100.0%, 0.142, 523.32 pg/mL, and p<0.001, respectively; and for miR-181a-5p were 100%, 11.1%, 0.201, 1.00 and p<0.001, respectively. These results are presented in Table 5 and Figure 2 . Table 5. Diagnostic performance of biomarkers and miR-181. Group Sensitivity % Specificity % 95% Confidence Interval Area ± SE Cutoff P value MIF 80.6 100.0 0.803 – 0.944 0.873 ± 0.036 80.10 0.000 * TNFAIP3 6.9 100.0 0.067 – 0.217 0.142 ± 0.038 523.32 0.000 * CXCR4 81.9 100.0 0.878 – 0.980 0.929 ± 0.026 68.10 0.000 * miR-181a-5p 100.0 11.1 0.044 – 0.358 0.201 ± 0.080 1 0.000 * * p < 0.001 Figure 2. ROC curves of MIF, TNFAIP3, CXCR4, and miR-181a-5p in CML patients. miR-181 and biomarker interactions Bioinformatics analysis of miR-181a target interactions and regulatory pathways The TNFAIP3 gene was predicted to be a likely direct target of hsa-miR-181a-5p in silico ( Figure 3 ). Target prediction was carried out with miRWalk 3.0 (version 2018 release), TargetScanHuman 8.0, and miRDB (version 6.0). The prediction was made with a minimum free energy (MFE) threshold ≤ -15 kcal/mol, binding probability ≥ 0.70, and seed region complementarity of ≥ 7 consecutive nucleotides. In miRWalk, miR-181a-5p had a noteworthy binding site within the CDS of TNFAIP3 mRNA at positions 394–406 with an MFE of -18.5 kcal/mol and a binding probability of 0.923. The predicted duplex has 11 consecutive base pairs in a 12-base region indicating a stable and efficient interaction. However, TNFAIP3 was not predicted to be a target by TargetScan or miRDB which underscores the differences in the databases. Functionally TNFAIP3 is a known negative regulator of NF-κB signaling. Suppression of TNFAIP3 by miR-181a-5p would relieve this inhibition and thus, promote NF-κB activity. Functional enrichment and network analyses were performed by STRING (version 12.0) and NDExBio which showed MIF and CXCR4 to be downstream targets of NF-κB. There were no sites of direct binding predicted for miR-181a-5p with MIF or CXCR4 in the prediction databases, but the results outlined above indicate that miR-181a-5p is also increased MIF and CXCR4 levels by indirectly targeting and downregulating TNFAIP3 thus stimulating inflammatory signaling pathways involved in the pathogenesis of CML. Figure 3. Bioinformatic model of miR-181a-mediated post-transcriptional regulation of TNFAIP3 and its downstream impact on NF-κB signaling, MIF, and CXCR4 expression in CML. Discussion Chronic myeloid leukemia (CML) is characterized by a disturbance of normal hematopoiesis, which is supported by the hematological findings noted in the study which include anemia, leukocytosis, and thrombocytopenia. 14 These changes, which show that BCR-ABL1 oncogenic signaling is the root cause of bone marrow failure, are similar to what has been shown in other studies conducted in Iraq and in large-scale cohorts around the world. More evidence is pointing to the important function of microRNAs (miRNAs) in controlling cancer pathways, inflammatory reactions, and treatment resistance in CML. 15 – 17 A possible oncogenic role was highlighted by the study finding that miR-181a expression was significantly upregulated in CML patients compared to healthy controls. The observed elevation in newly diagnosed, untreated CML cases is consistent with findings that demonstrate context-dependent dynamic regulation of miR-181a, 18 even though some studies, including reports from worldwide datasets, have shown a downregulation of miR-181a in TKI-sensitive patients. 19 Crucially the results of the bioinformatics study showed that miR-181a directly targets TNFAIP3 lending credence to the idea that an overexpression of miR-181a might reduce TNFAIP3 expression, which in turn would cause the NF-κB pathway to remain activated. Previous functional investigations have shown that leukemic cell survival and inflammatory signaling are both enhanced when TNFAIP3 activity is lost, and this molecular relationship is in agreement with those findings. 20 This regulation model was further supported by correlation analysis which showed that miR-181a expression was positively connected with MIF and CXCR4 levels and inversely correlated with TNFAIP3. 21 Prior research has shown that MIF enhances leukemic cell survival and accelerates chemokine-mediated migration via CXCR4 which is supported by the increased levels of MIF seen in CML patients. Simultaneously, the study’s identification of CXCR4 overexpression lends credence to the crucial function of the CXCR4/SDF-1 axis in preserving leukemic stem cells within protected bone marrow niches, which in turn contributes to the perpetuation of disease and resistance to therapy. 22 , 23 These results are consistent with what researchers in Iraq and around the world have found, which further proves that these pathways are important in the development of CML everywhere. 24 The results are new and significant for the area research environment because few studies have thoroughly assessed the diagnostic performance of miR-181a in conjunction with inflammatory biomarkers in CML. This study fills a gap in the literature by offering a thorough integrated examination of the relationship between miRNA dysregulation and inflammatory signaling pathways in CML patients, in contrast to earlier sparse studies from Iraq. 25 – 27 Based on the results of this study, a possible mechanism is that an increase in miR-181a inhibits TNFAIP3, which in turn activates NF-κB signaling and increases the levels of inflammatory and chemotactic effectors including MIF and CXCR4. Further research with bigger patient cohorts and functional validation assays is needed to confirm these findings and investigate their therapeutic implications, although the study does provide strong evidence for the involvement of the miR-181a/TNFAIP3/MIF/CXCR4 axis in CML pathogenesis. Novel approaches to treating treatment resistance and enhancing clinical outcomes in CML patients may be revealed by future studies that focus on this regulatory network. In conclusion, the study revealed that miR-181a plays a crucial role in CML pathogenesis via regulating TNFAIP3 and other downstream inflammatory mediators. These results expand the study molecular knowledge of CML and point to potential areas for future diagnostic and treatment advancements, especially for patients in Iraq and the surrounding area. Data availability statement Zenodo: Dysregulation of MicroRNA-181a-5p Targets TNFAIP3 to Promote MIF-CXCR4 Signaling and Immune Inflammatory Remodeling in Chronic Myeloid Leukemia. https://doi.org/10.5281/zenodo.17653441 . 28 This project contains the following underlying data: • CML.xlsx: This single dataset contains all raw and processed data used in the statistical analyses, including hematological parameters (Hb, RBC, WBC, PLT), serum biomarker measurements (MIF, TNFAIP3, CXCR4), and qPCR data (RNU43 Ct, miR-181a Ct, ΔCt, ΔΔCt, and fold-change values). • Participant questionnaire: Used during sample collection. 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Publisher Full Text Comments on this article Comments (0) Version 3 VERSION 3 PUBLISHED 26 Dec 2025 ADD YOUR COMMENT Comment Author details Author details 1 Pathology, Al Iraqia University College of Medicine, baghdad, 3, 10079, Iraq 2 Department of Molecular and Medical Biotechnology, College of Biotechnology, Al-Nahrain University, baghdad, 3, 10079, Iraq 3 College of Health and Medical Techniques/ Baghdad, Middle Technical University, baghdad, 3, 10079, Iraq 4 Biology, Middle East University, baghdad, 3, 10079, Iraq Noha Mohammed Saleh Roles: Data Curation, Funding Acquisition, Methodology, Project Administration Rawaa AlChalabi Roles: Project Administration, Resources, Supervision, Visualization, Writing – Review & Editing Yasir Issa Roles: Formal Analysis, Writing – Original Draft Preparation, Writing – Review & Editing Shahad Nassurat Roles: Funding Acquisition, Investigation Competing interests No competing interests were disclosed. Grant information The author(s) declared that no grants were involved in supporting this work. Article Versions (3) version 3 Revised Published: 26 Mar 2026, 14:1460 https://doi.org/10.12688/f1000research.172236.3 version 2 Revised Published: 05 Feb 2026, 14:1460 https://doi.org/10.12688/f1000research.172236.2 version 1 Published: 26 Dec 2025, 14:1460 https://doi.org/10.12688/f1000research.172236.1 Copyright © 2025 Mohammed Saleh N et al . This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The author(s) is/are employees of the US Government and therefore domestic copyright protection in USA does not apply to this work. The work may be protected under the copyright laws of other jurisdictions when used in those jurisdictions. Download Export To Sciwheel Bibtex EndNote ProCite Ref. Manager (RIS) Sente metrics Views Downloads F1000Research - - PubMed Central info_outline Data from PMC are received and updated monthly. - - Citations open_in_new 0 open_in_new 0 open_in_new SEE MORE DETAILS CITE how to cite this article Mohammed Saleh N, AlChalabi R, Issa Y and Nassurat S. Dysregulation of MicroRNA-181a-5p Targets TNFAIP3 to Promote MIF-CXCR4 Signaling and Immune Inflammatory Remodeling in Chronic Myeloid Leukemia [version 1; peer review: 2 approved with reservations] . F1000Research 2025, 14 :1460 ( https://doi.org/10.12688/f1000research.172236.1 ) NOTE: If applicable, it is important to ensure the information in square brackets after the title is included in all citations of this article. COPY CITATION DETAILS track receive updates on this article Track an article to receive email alerts on any updates to this article. TRACK THIS ARTICLE Share Open Peer Review Current Reviewer Status: ? Key to Reviewer Statuses VIEW HIDE Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions Version 1 VERSION 1 PUBLISHED 26 Dec 2025 Views 0 Cite How to cite this report: Zhang h and He A. Reviewer Report For: Dysregulation of MicroRNA-181a-5p Targets TNFAIP3 to Promote MIF-CXCR4 Signaling and Immune Inflammatory Remodeling in Chronic Myeloid Leukemia [version 1; peer review: 2 approved with reservations] . F1000Research 2025, 14 :1460 ( https://doi.org/10.5256/f1000research.189951.r448884 ) The direct URL for this report is: https://f1000research.com/articles/14-1460/v1#referee-response-448884 NOTE: it is important to ensure the information in square brackets after the title is included in this citation. Close Copy Citation Details Reviewer Report 23 Jan 2026 haijiao Zhang , Oregon Health & Science University, Portland, Oregon, USA Anna He , Division of Oncological Sciences, Oregon Health & Science University Knight Cancer Institute (Ringgold ID: 608031), Portland, Oregon, USA Approved with Reservations VIEWS 0 https://doi.org/10.5256/f1000research.189951.r448884 Dysregulation of MicroRNA-181a-5p Targets TNFAIP3 to Promote MIF-CXCR4 Signaling and Immune Inflammatory Remodeling in Chronic Myeloid Leukemia Noha Mohammed Saleh 1 , Rawaa AlChalabi 2 , Yasir Issa 3 , Shahad Nassurat 4 Comments to the Author: The study by Noha Mohammed ... Continue reading READ ALL Dysregulation of MicroRNA-181a-5p Targets TNFAIP3 to Promote MIF-CXCR4 Signaling and Immune Inflammatory Remodeling in Chronic Myeloid Leukemia Noha Mohammed Saleh 1 , Rawaa AlChalabi 2 , Yasir Issa 3 , Shahad Nassurat 4 Comments to the Author: The study by Noha Mohammed Saleh et al. evaluated gene expression of miR-181a and serum concentrations of biomarkers MIF, TNFAIP3, and CXCR4 in CML patients compared to healthy controls, assessing interactions between miR-181a and target genes. They demonstrated that miR-181a expression was significantly upregulated in CML patients and directly targets TNFAIP3. A proposed mechanism is that increased miR-181a expression inhibits TNFAIP3, activating NF-κB signaling and regulating downstream inflammatory mediators such as MIF and CXCR4. They conclude that miR-181a plays a crucial role in CML pathogenesis through regulation of TNFAIP3 and other downstream inflammatory mediators. The following major and minor questions should be addressed or corrected accordingly. Major Questions This study is primarily descriptive and does not include experimental validation. Accordingly, the conclusions should be interpreted as hypothesis-generating, with proposed mechanisms, biomarkers, and downstream targets considered putative and requiring further molecular and functional validation. Conclusion such as mentioned in the discussion that: A possible oncogenic role was highlighted by the study finding that miR-181a expression was significantly upregulated in CML patients compared to healthy controls. This claim is inaccurate; oncogenic properties were not assessed, and no relationship between oncogenic activity and miR-181a expression was demonstrated. In addition, at the end of the discussion, the author wrote that: In conclusion, the study revealed that miR-181a plays a crucial role in CML pathogenesis via regulating TNFAIP3 and other downstream inflammatory mediators. These results expand the study molecular knowledge of CML and point to potential areas for future diagnostic and treatment advancements, especially for patients in Iraq and the surrounding area. This statement is inaccurate, as the study is descriptive and reports only increased miR-181a levels in CML patients, along with the potential diagnostic value of MIF and CXCR4 in CML; therefore, concluding that miR-181a plays a crucial role in CML pathogenesis is an overstatement. Minor Criteria 1) Some parts of the writing need careful editing, such as punctuation and spacing in the Introduction and Discussion. Additionally, in the Introduction, abnormal NF-κB activation “improves the disease duration” of CML; however, the positive connotation of “improves” should be noted. The footnote to Table 1 seems to have additional unnecessary text. In the Abstract Conclusion, “MIFpresent3” is incorrect. Collectively, this study suggests a novel pathogenic mechanism involving immune dysregulation in CML through identification of miR-181a, MIF, and CXCR4 in immune modulation and inflammation. 2) There is an inconsistency between the Introduction, References, and Results. In the Introduction, the authors state that “CML stem/progenitor cells downregulate miR-181a expression, making them more susceptible to apoptosis and TKIs,” but no citation is provided to support this claim. Moreover, this statement is inconsistent with the study’s findings showing that miR-181a is upregulated in CML patients in your cohort. 3) In the paragraph below, the reported correlation coefficients (R = 0.617 and R = 0.630, both p < 0.05) indicate strong correlations rather than a “slight association.” Correlation between miR-181 expression and biomarkers In the study population, the Pearson correlation analysis showed a slight association between the miR-181-fold change and the levels of MIF (r = 0.617, p < 0.0001) and CXCR4 (r = 0.630, p < 0.0001). The expression of miR-181 was shown to be strongly correlated negatively with TNFAIP3 levels (r = -0.758, p < 0.0001). Based on these results it appears that CML-specific inflammatory and chemokine signaling patterns are linked to miR-181 expression. As reported in Table 4 . Is the work clearly and accurately presented and does it cite the current literature? Partly Is the study design appropriate and is the work technically sound? Partly Are sufficient details of methods and analysis provided to allow replication by others? Partly If applicable, is the statistical analysis and its interpretation appropriate? Partly Are all the source data underlying the results available to ensure full reproducibility? Partly Are the conclusions drawn adequately supported by the results? Partly Competing Interests: No competing interests were disclosed. Reviewer Expertise: Leukemia, translation oncology, drug resistance mechanisms. We confirm that we have read this submission and believe that we have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however we have significant reservations, as outlined above. Close READ LESS CITE CITE HOW TO CITE THIS REPORT Zhang h and He A. Reviewer Report For: Dysregulation of MicroRNA-181a-5p Targets TNFAIP3 to Promote MIF-CXCR4 Signaling and Immune Inflammatory Remodeling in Chronic Myeloid Leukemia [version 1; peer review: 2 approved with reservations] . F1000Research 2025, 14 :1460 ( https://doi.org/10.5256/f1000research.189951.r448884 ) The direct URL for this report is: https://f1000research.com/articles/14-1460/v1#referee-response-448884 NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article. COPY CITATION DETAILS Report a concern Respond or Comment COMMENT ON THIS REPORT Views 0 Cite How to cite this report: Rinaldi I. Reviewer Report For: Dysregulation of MicroRNA-181a-5p Targets TNFAIP3 to Promote MIF-CXCR4 Signaling and Immune Inflammatory Remodeling in Chronic Myeloid Leukemia [version 1; peer review: 2 approved with reservations] . F1000Research 2025, 14 :1460 ( https://doi.org/10.5256/f1000research.189951.r446680 ) The direct URL for this report is: https://f1000research.com/articles/14-1460/v1#referee-response-446680 NOTE: it is important to ensure the information in square brackets after the title is included in this citation. Close Copy Citation Details Reviewer Report 08 Jan 2026 Ikhwan Rinaldi , Cipto Mangunkusumo Hospital, Central Jakarta, Universitas Indonesia, Jakarta, Indonesia Approved with Reservations VIEWS 0 https://doi.org/10.5256/f1000research.189951.r446680 The manuscript addresses the role of miR-181a-5p–mediated regulation of TNFAIP3 and its downstream inflammatory signaling pathways in chronic myeloid leukemia (CML). Several issues should be addressed before the manuscript can be considered for indexing. Abstract ... Continue reading READ ALL The manuscript addresses the role of miR-181a-5p–mediated regulation of TNFAIP3 and its downstream inflammatory signaling pathways in chronic myeloid leukemia (CML). Several issues should be addressed before the manuscript can be considered for indexing. Abstract In the Methods section, please clearly state the study design (case–control), the main laboratory techniques employed (qRT-PCR and ELISA), and the statistical tests used. In the Results section, if possible, key quantitative findings should be summarized more explicitly, including effect sizes or fold changes with corresponding p-values for miR-181a, MIF, TNFAIP3, and CXCR4. Methods and Results The sample size justification is not described. Please clarify whether a priori sample size or power calculations were performed to ensure adequate statistical power. The statistical analysis relies heavily on independent t-tests. Please confirm that assumptions of normality and variance homogeneity were assessed, or alternatively justify the use of non-parametric tests where appropriate. Figure 2 (ROC curves) would benefit from clearer annotation. Please consider adding arrows or labels indicating the AUC values for each biomarker directly on the figure. Abbreviations should be consistently defined in all tables and figure captions. Discussion The authors are encouraged to expand the limitations section to include the single-center design, relatively modest sample size, and population specificity, which may affect generalizability. Is the work clearly and accurately presented and does it cite the current literature? Yes Is the study design appropriate and is the work technically sound? Yes Are sufficient details of methods and analysis provided to allow replication by others? Partly If applicable, is the statistical analysis and its interpretation appropriate? Yes Are all the source data underlying the results available to ensure full reproducibility? Yes Are the conclusions drawn adequately supported by the results? Yes Competing Interests: No competing interests were disclosed. Reviewer Expertise: Hemato-oncology I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above. Close READ LESS CITE CITE HOW TO CITE THIS REPORT Rinaldi I. Reviewer Report For: Dysregulation of MicroRNA-181a-5p Targets TNFAIP3 to Promote MIF-CXCR4 Signaling and Immune Inflammatory Remodeling in Chronic Myeloid Leukemia [version 1; peer review: 2 approved with reservations] . F1000Research 2025, 14 :1460 ( https://doi.org/10.5256/f1000research.189951.r446680 ) The direct URL for this report is: https://f1000research.com/articles/14-1460/v1#referee-response-446680 NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article. COPY CITATION DETAILS Report a concern Respond or Comment COMMENT ON THIS REPORT Comments on this article Comments (0) Version 3 VERSION 3 PUBLISHED 26 Dec 2025 ADD YOUR COMMENT Comment keyboard_arrow_left keyboard_arrow_right Open Peer Review Reviewer Status info_outline Alongside their report, reviewers assign a status to the article: Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions Reviewer Reports Invited Reviewers 1 2 3 Version 3 (revision) 26 Mar 26 read Version 2 (revision) 05 Feb 26 read read Version 1 26 Dec 25 read read Ikhwan Rinaldi , Universitas Indonesia, Jakarta, Indonesia haijiao Zhang , Oregon Health & Science University, Portland, USA Anna He , Oregon Health & Science University Knight Cancer Institute (Ringgold ID: 608031), Portland, USA Dan Jones , Ohio State University James Comprehensive Cancer Center, Columbus, USA Ryan Stevens , The Ohio State University Comprehensive Cancer Center Arthur G James Cancer Hospital and Richard J Solove Research Institute (Ringgold ID: 24600), Columbus, USA Comments on this article All Comments (0) Add a comment Sign up for content alerts Sign Up You are now signed up to receive this alert Browse by related subjects keyboard_arrow_left Back to all reports Reviewer Report 0 Views copyright © 2026 Jones D et al. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 06 Apr 2026 | for Version 3 Dan Jones , Ohio State University James Comprehensive Cancer Center, Columbus, Ohio, USA Ryan Stevens , The Ohio State University Comprehensive Cancer Center Arthur G James Cancer Hospital and Richard J Solove Research Institute (Ringgold ID: 24600), Columbus, Ohio, USA 0 Views copyright © 2026 Jones D et al. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. format_quote Cite this report speaker_notes Responses (0) Approved With Reservations info_outline Alongside their report, reviewers assign a status to the article: Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions Saleh et al present a case control study comprising 57 CML patients (vs 33 age/sex-matched controls) assessing miR-181a expression in serum by qRT-PCR as compared to serum levels of a NF-kB growth factor inhibitor (TNFAIP3) and a chemokine and a chemokine receptor (MIF and CXCR4, respectively) by ELISA. They show that miR-181a transcripts are upregulated in the serum of stable phase untreated CML as were MIF and CXCR4 protein levels whereas TNFAIP3 was decreased (previously shown in one prior study cited). Using bioinformatic analysis of the TNFAIP3 transcript, the Authors postulate that MiR-181a may be directly downregulating TNFAIP3 leading to activation of NF-kB pathway and chemokine upregulation. Major Points to Address: Abstract - This sentence is confusing and should be rewritten since TNFAIP3 and miR-181a just don’t predict for CML in your study: “ROC analysis showed that MIF (AUC =0.873) and CXCR4 (AUC = 0.929) exhibited strong diagnostic performance while TNFAIP3 (AUC = 0.142) and miR-181a-5p (AUC = 0.201) demonstrated weak accuracy consistent with their opposite expression patterns between CML patients and healthy controls.” You could just mention MIF and CXCR4 and leave out the other two in the abstract and just discuss their performance in the results. Methods: Was RNA really extracted from “serum” (not buffy coat or plasma) using Trizol? If so, I highly doubt the levels of miRs are going to be reflective of the cellular component. If this is true, this needs to be prominently mentioned in results such as “significantly higher transcript levels of miR-181 (2.28) in serum , and also mentioned this in the abstract. The discussion should note that serum miRs may not reflect cellular levels, as a possible problem with the study Discussion: There is too direct a connection made between MIF and CXCR4 levels and NF-kB activation due to TNFAIP3 decreases. Both of these chemokine pathways are also highly regulated by other growth factors. Please add some caveats about this connection to the Discussion. You should also mention that miR-181 is known to regulate other important growth regulatory pathways in CML cells which could also be contributing to these observations. Also, CML is characterized by increased IMMATURE myeloid cells compared to normal hematopoiesis. Since immature myeloid cells have markedly increased CXCR4 and MIF (compared to neutrophils), the correlations observed may be reflective of the disease and not caused by miR-181 directly. Add something about this to the Discussion, Given the lack of functional validation of the in silico analysis of TNFAIP3, I would also add to the Discussion, literature on the connection between miR-181a in leukemic cell models (there is data in CLL and other leukemic models). Sample size is small so your comment in the Discussion on needing validation in a larger cohort should also be in the abstract. There are still spelling grammar, spacing, and wording issues throughout. For example in Introduction: “bind to” not “fix to” matching sequences; “3’ prime” not “3 prim”; “contributing” not “contributes” to disease progression and persistence. Write “miR-181a” consistently throughout as far as capitalization if at sentence start. Please grammar and spell check the entire document. Minor Points to Address: Title: I would say “MIF and CXR4 signaling (not “MIF-CXCR4”) since these are not in the same chemokine family Methods: Mention how many (if any) of the CML patients had prior treatment and the median treatment interval before the sample used (even short treatments can greatly affect NF-kB and chemokine pathways). Methods: Mention whether replicate measurement were made by qRT-PCR and/or by ELISA. Results: I would remove “Signifying increased macrophage activation,” since MIF is expressed widely (DCs, CML myeloid cells) since its elevation isn’t proof of macrophage activation. Discussion: Add paragraph breaks, to make the comments easier to read (as well as adding discussion of the points above). Is the work clearly and accurately presented and does it cite the current literature? Partly Is the study design appropriate and is the work technically sound? Yes Are sufficient details of methods and analysis provided to allow replication by others? Yes If applicable, is the statistical analysis and its interpretation appropriate? Partly Are all the source data underlying the results available to ensure full reproducibility? Yes Are the conclusions drawn adequately supported by the results? Partly Competing Interests No competing interests were disclosed. Reviewer Expertise CML, immunology, molecular diagnostics (Jones), molecular diagnostics (Ryan Stevens, who contributed to this review). We confirm that we have read this submission and believe that we have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however we have significant reservations, as outlined above. reply Respond to this report Responses (0) Jones D and Stevens R. Peer Review Report For: Dysregulation of MicroRNA-181a-5p Targets TNFAIP3 to Promote MIF-CXCR4 Signaling and Immune Inflammatory Remodeling in Chronic Myeloid Leukemia [version 1; peer review: 2 approved with reservations] . F1000Research 2025, 14 :1460 ( https://doi.org/10.5256/f1000research.197132.r471436) NOTE: it is important to ensure the information in square brackets after the title is included in this citation. The direct URL for this report is: https://f1000research.com/articles/14-1460/v3#referee-response-471436 keyboard_arrow_left Back to all reports Reviewer Report 0 Views copyright © 2026 Rinaldi I. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 24 Feb 2026 | for Version 2 Ikhwan Rinaldi , Cipto Mangunkusumo Hospital, Central Jakarta, Universitas Indonesia, Jakarta, Indonesia 0 Views copyright © 2026 Rinaldi I. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. format_quote Cite this report speaker_notes Responses (2) Approved With Reservations info_outline Alongside their report, reviewers assign a status to the article: Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions Thank you for the revisions. However, the following key concerns remain unaddressed and should be resolved: 1. The revised manuscript still does not provide a justification for the chosen sample size, nor does it report any a priori power or sample size calculations. Please clarify whether a power analysis was performed and, if not, provide a rationale for the selected sample size and discuss its implications for the statistical robustness of the findings. 2. Independent t-tests continue to be used as the primary statistical method. However, the manuscript does not report whether assumptions of normality and homogeneity of variance were assessed. Please specify how these assumptions were evaluated or justify the continued use of parametric tests. Competing Interests No competing interests were disclosed. Reviewer Expertise Hemato-oncology I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above. reply Respond to this report Responses (2) Author Response 26 Mar 2026 Yasir Issa, Reasarch Unit, Middle Technical University, Baghdad, Iraq In this revised version, we have further strengthened the statistical methodology in response to reviewer comments. Specifically, we have clarified the assessment of assumptions underlying parametric testing by explicitly reporting the use of the Shapiro–Wilk test and Q–Q plots to evaluate normality, as well as Levene’s test to assess homogeneity of variances. We have also indicated that Welch’s correction was applied when appropriate. In addition, a post-hoc power analysis has been included to justify the adequacy of the sample size. The calculated statistical power (1−β = 0.98) confirms that the study was sufficiently powered to detect significant group differences. We have also clarified the presentation of descriptive statistics, specifying that data are expressed as mean ± standard error (SE) to reflect the precision of the estimated mean. These additions enhance the transparency, robustness, and methodological clarity of the study without altering the original results or conclusions. View more View less Competing Interests No competing interests were disclosed. reply Respond Report a concern Author Response 26 Mar 2026 Yasir Issa, Reasarch Unit, Middle Technical University, Baghdad, Iraq thank you for your valuable comments. We have now clarified the statistical considerations in the revised manuscript. A sensitivity analysis was conducted using G*Power (v3.1) based on the available sample size (33 participants in group 1 and 57 in group 2). With an alpha level of 0.05 and statistical power of 0.90, the analysis indicated that the study was capable of detecting an effect size of d = 0.72, which corresponds to a medium-to-large effect according to Cohen’s criteria. This information has now been added to the Statistical Analysis section. In addition, we have clarified that the assumptions required for parametric testing were evaluated prior to analysis. Normality of the data was assessed using the Shapiro–Wilk test, and homogeneity of variance between groups was examined using Levene’s test. Independent-samples t-tests were applied after confirming that these assumptions were satisfied. View more View less Competing Interests No competing interests were disclosed. reply Respond Report a concern Rinaldi I. Peer Review Report For: Dysregulation of MicroRNA-181a-5p Targets TNFAIP3 to Promote MIF-CXCR4 Signaling and Immune Inflammatory Remodeling in Chronic Myeloid Leukemia [version 1; peer review: 2 approved with reservations] . F1000Research 2025, 14 :1460 ( https://doi.org/10.5256/f1000research.195767.r455867) NOTE: it is important to ensure the information in square brackets after the title is included in this citation. The direct URL for this report is: https://f1000research.com/articles/14-1460/v2#referee-response-455867 keyboard_arrow_left Back to all reports Reviewer Report 0 Views copyright © 2026 Zhang h. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 23 Feb 2026 | for Version 2 haijiao Zhang , Oregon Health & Science University, Portland, Oregon, USA 0 Views copyright © 2026 Zhang h. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. format_quote Cite this report speaker_notes Responses (0) Approved info_outline Alongside their report, reviewers assign a status to the article: Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions The revision adequately addressed the previous concerns. Competing Interests No competing interests were disclosed. I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard. reply Respond to this report Responses (0) Zhang h. Peer Review Report For: Dysregulation of MicroRNA-181a-5p Targets TNFAIP3 to Promote MIF-CXCR4 Signaling and Immune Inflammatory Remodeling in Chronic Myeloid Leukemia [version 1; peer review: 2 approved with reservations] . F1000Research 2025, 14 :1460 ( https://doi.org/10.5256/f1000research.195767.r455868) NOTE: it is important to ensure the information in square brackets after the title is included in this citation. The direct URL for this report is: https://f1000research.com/articles/14-1460/v2#referee-response-455868 keyboard_arrow_left Back to all reports Reviewer Report 0 Views copyright © 2026 Zhang h et al. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 23 Jan 2026 | for Version 1 haijiao Zhang , Oregon Health & Science University, Portland, Oregon, USA Anna He , Division of Oncological Sciences, Oregon Health & Science University Knight Cancer Institute (Ringgold ID: 608031), Portland, Oregon, USA 0 Views copyright © 2026 Zhang h et al. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. format_quote Cite this report speaker_notes Responses (0) Approved With Reservations info_outline Alongside their report, reviewers assign a status to the article: Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions Dysregulation of MicroRNA-181a-5p Targets TNFAIP3 to Promote MIF-CXCR4 Signaling and Immune Inflammatory Remodeling in Chronic Myeloid Leukemia Noha Mohammed Saleh 1 , Rawaa AlChalabi 2 , Yasir Issa 3 , Shahad Nassurat 4 Comments to the Author: The study by Noha Mohammed Saleh et al. evaluated gene expression of miR-181a and serum concentrations of biomarkers MIF, TNFAIP3, and CXCR4 in CML patients compared to healthy controls, assessing interactions between miR-181a and target genes. They demonstrated that miR-181a expression was significantly upregulated in CML patients and directly targets TNFAIP3. A proposed mechanism is that increased miR-181a expression inhibits TNFAIP3, activating NF-κB signaling and regulating downstream inflammatory mediators such as MIF and CXCR4. They conclude that miR-181a plays a crucial role in CML pathogenesis through regulation of TNFAIP3 and other downstream inflammatory mediators. The following major and minor questions should be addressed or corrected accordingly. Major Questions This study is primarily descriptive and does not include experimental validation. Accordingly, the conclusions should be interpreted as hypothesis-generating, with proposed mechanisms, biomarkers, and downstream targets considered putative and requiring further molecular and functional validation. Conclusion such as mentioned in the discussion that: A possible oncogenic role was highlighted by the study finding that miR-181a expression was significantly upregulated in CML patients compared to healthy controls. This claim is inaccurate; oncogenic properties were not assessed, and no relationship between oncogenic activity and miR-181a expression was demonstrated. In addition, at the end of the discussion, the author wrote that: In conclusion, the study revealed that miR-181a plays a crucial role in CML pathogenesis via regulating TNFAIP3 and other downstream inflammatory mediators. These results expand the study molecular knowledge of CML and point to potential areas for future diagnostic and treatment advancements, especially for patients in Iraq and the surrounding area. This statement is inaccurate, as the study is descriptive and reports only increased miR-181a levels in CML patients, along with the potential diagnostic value of MIF and CXCR4 in CML; therefore, concluding that miR-181a plays a crucial role in CML pathogenesis is an overstatement. Minor Criteria 1) Some parts of the writing need careful editing, such as punctuation and spacing in the Introduction and Discussion. Additionally, in the Introduction, abnormal NF-κB activation “improves the disease duration” of CML; however, the positive connotation of “improves” should be noted. The footnote to Table 1 seems to have additional unnecessary text. In the Abstract Conclusion, “MIFpresent3” is incorrect. Collectively, this study suggests a novel pathogenic mechanism involving immune dysregulation in CML through identification of miR-181a, MIF, and CXCR4 in immune modulation and inflammation. 2) There is an inconsistency between the Introduction, References, and Results. In the Introduction, the authors state that “CML stem/progenitor cells downregulate miR-181a expression, making them more susceptible to apoptosis and TKIs,” but no citation is provided to support this claim. Moreover, this statement is inconsistent with the study’s findings showing that miR-181a is upregulated in CML patients in your cohort. 3) In the paragraph below, the reported correlation coefficients (R = 0.617 and R = 0.630, both p < 0.05) indicate strong correlations rather than a “slight association.” Correlation between miR-181 expression and biomarkers In the study population, the Pearson correlation analysis showed a slight association between the miR-181-fold change and the levels of MIF (r = 0.617, p < 0.0001) and CXCR4 (r = 0.630, p < 0.0001). The expression of miR-181 was shown to be strongly correlated negatively with TNFAIP3 levels (r = -0.758, p < 0.0001). Based on these results it appears that CML-specific inflammatory and chemokine signaling patterns are linked to miR-181 expression. As reported in Table 4 . Is the work clearly and accurately presented and does it cite the current literature? Partly Is the study design appropriate and is the work technically sound? Partly Are sufficient details of methods and analysis provided to allow replication by others? Partly If applicable, is the statistical analysis and its interpretation appropriate? Partly Are all the source data underlying the results available to ensure full reproducibility? Partly Are the conclusions drawn adequately supported by the results? Partly Competing Interests No competing interests were disclosed. Reviewer Expertise Leukemia, translation oncology, drug resistance mechanisms. We confirm that we have read this submission and believe that we have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however we have significant reservations, as outlined above. reply Respond to this report Responses (0) Zhang h and He A. Peer Review Report For: Dysregulation of MicroRNA-181a-5p Targets TNFAIP3 to Promote MIF-CXCR4 Signaling and Immune Inflammatory Remodeling in Chronic Myeloid Leukemia [version 1; peer review: 2 approved with reservations] . F1000Research 2025, 14 :1460 ( https://doi.org/10.5256/f1000research.189951.r448884) NOTE: it is important to ensure the information in square brackets after the title is included in this citation. The direct URL for this report is: https://f1000research.com/articles/14-1460/v1#referee-response-448884 keyboard_arrow_left Back to all reports Reviewer Report 0 Views copyright © 2026 Rinaldi I. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 08 Jan 2026 | for Version 1 Ikhwan Rinaldi , Cipto Mangunkusumo Hospital, Central Jakarta, Universitas Indonesia, Jakarta, Indonesia 0 Views copyright © 2026 Rinaldi I. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. format_quote Cite this report speaker_notes Responses (0) Approved With Reservations info_outline Alongside their report, reviewers assign a status to the article: Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions The manuscript addresses the role of miR-181a-5p–mediated regulation of TNFAIP3 and its downstream inflammatory signaling pathways in chronic myeloid leukemia (CML). Several issues should be addressed before the manuscript can be considered for indexing. Abstract In the Methods section, please clearly state the study design (case–control), the main laboratory techniques employed (qRT-PCR and ELISA), and the statistical tests used. In the Results section, if possible, key quantitative findings should be summarized more explicitly, including effect sizes or fold changes with corresponding p-values for miR-181a, MIF, TNFAIP3, and CXCR4. Methods and Results The sample size justification is not described. Please clarify whether a priori sample size or power calculations were performed to ensure adequate statistical power. The statistical analysis relies heavily on independent t-tests. Please confirm that assumptions of normality and variance homogeneity were assessed, or alternatively justify the use of non-parametric tests where appropriate. Figure 2 (ROC curves) would benefit from clearer annotation. Please consider adding arrows or labels indicating the AUC values for each biomarker directly on the figure. Abbreviations should be consistently defined in all tables and figure captions. Discussion The authors are encouraged to expand the limitations section to include the single-center design, relatively modest sample size, and population specificity, which may affect generalizability. Is the work clearly and accurately presented and does it cite the current literature? Yes Is the study design appropriate and is the work technically sound? Yes Are sufficient details of methods and analysis provided to allow replication by others? Partly If applicable, is the statistical analysis and its interpretation appropriate? Yes Are all the source data underlying the results available to ensure full reproducibility? Yes Are the conclusions drawn adequately supported by the results? Yes Competing Interests No competing interests were disclosed. Reviewer Expertise Hemato-oncology I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above. reply Respond to this report Responses (0) Rinaldi I. Peer Review Report For: Dysregulation of MicroRNA-181a-5p Targets TNFAIP3 to Promote MIF-CXCR4 Signaling and Immune Inflammatory Remodeling in Chronic Myeloid Leukemia [version 1; peer review: 2 approved with reservations] . F1000Research 2025, 14 :1460 ( https://doi.org/10.5256/f1000research.189951.r446680) NOTE: it is important to ensure the information in square brackets after the title is included in this citation. The direct URL for this report is: https://f1000research.com/articles/14-1460/v1#referee-response-446680 Alongside their report, reviewers assign a status to the article: Approved - the paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations - A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved - fundamental flaws in the paper seriously undermine the findings and conclusions Adjust parameters to alter display View on desktop for interactive features Includes Interactive Elements View on desktop for interactive features Competing Interests Policy Provide sufficient details of any financial or non-financial competing interests to enable users to assess whether your comments might lead a reasonable person to question your impartiality. 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