Cross-Sectional Study: Associations of A20 and Cezanne with Leukocyte Accumulation in B-Cell Acute Lymphoblastic Leukemia
Abstract
1. Introduction
2. Materials and Methods
2.1. Patients and Control Subjects
2.2. DNA Sequencing of A20, CYLD and Cezanne Genes
2.3. Cytokine Quantification
2.4. RNA Extraction and Real-Time RT-PCR
2.5. Immunostaining and Flow Cytometry
2.6. Data Analysis
2.7. Statistics
3. Results
3.1. Clinical Associations and Immunophenotype in B-ALL Patients
3.2. DNA Sequencing of A20, Cezanne and CYLD Genes in B-ALL Patients
3.3. Associations of the A20 Expression and Polymorphisms with Clinical Characteristics and Immunophenotype in B-ALL Patients
4. Discussion
5. Conclusions
Limitations
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
Abbreviations
ALL | Acute lymphoblastic leukemia |
ALT | Alanine aminotransferase |
AST | Aspartate transaminase |
BM | Bone marrow |
CYLD | Cylindromatosis |
DUB | Deubiquitinases |
GAPDH | Glyceraldehyde-3-Phosphate Dehydrogenase |
GGT | Gamma glutamyl transferase |
HWE | Hardy–Weinberg equilibrium |
IL-6 | Interleukin-6 |
NK | Natural Killer |
LDH | Lactate dehydrogenase |
MAF | Minor allele frequency |
NF-κB | Nuclear Factor-kappa B |
MAPK | Mitogen-activated protein kinase |
PCR | Polymerase Chain Reaction |
SNP | Single nucleotide polymorphism |
STAT | Signal transducer and activator of transcription |
TNFAIP3, A20 | Tumor necrosis factor-α (TNFα)-induced protein 3 |
TGF-β | Transforming growth factor-β |
TNF-α | Tumor necrosis factor-α |
Treg | Regulatory T-cells |
WBC | Ưhite blood cell |
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Characteristics | Normal Range | Total (n = 147) |
---|---|---|
Age (years) | 30.95 ± 21.7 | |
Sex. male (n. %) | 87 (59.18) | |
Urea (mmol/L) | 2.5–7.5 | 6 ± 3.38 |
Glucose (mmol/L) | 3.9–6.4 | 7.28 ± 7.47 |
Creatinine (µmol/L) | 62–120 | 86.17 ± 56.54 |
Uric acid (µmol/L) | 420 (M)/360 (F) | 460.48 ± 203.5 |
Total bilirubin (µmol/L) | ≤17 | 16.53 ± 25 |
Direct bilirunbin (µmol/L) | ≤4.3 | 5.63 ± 18.04 |
Indirect bilirubin (µmol/L) | ≤12.7 | 11.37 ± 8.98 |
Total protein (g/L) | 65–82 | 77.04 ± 63.06 |
Albumin (g/L) | 35–50 | 38.72 ± 5.18 |
Globulin (g/L) | 24–38 | 33.21 ± 6.44 |
Ferritin (µg/L) | 30–300 | 766.93 ± 494.14 |
AST (GOT) (U/L) | ≤37 | 63.8 ± 66.17 |
ALT (GPT) (U/L) | ≤40 | 44.8 ± 43.84 |
GGT (UI/L) | ≤60 | 150.22 ± 158.06 |
LDH (IU/L) | 230–460 | 2942.7 ± 4268.1 |
Erythrocyte count (T/L) | 3.9–5.03 | 3.89 ± 7.3 |
Hemoglobin (g/L) | 120–155 | 92.93 ± 24.87 |
Hematocrit (%) | 37–43 | 29 ± 7.45 |
Nucleated erythrocyte count (G/L) | 0 | 0.23 ± 0.56 |
Reticulocytes (%) | 0.5–1.5 | 1.45 ± 1.16 |
Platelet count (G/L) | 150–450 | 90.29 ± 100.5 |
WBC count (G/L) | 3.5–10.5 | 69.78 ± 105.65 |
BM blasts (%) | 0–20 | 70.95 ± 27.83 |
Neutrophil count (G/L) | 2.8–5.5 | 5.68 ± 17.2 |
Eosinophil count (G/L) | 0.16–0.8 | 0.23 ± 0.8 |
Basophil count (G/L) | 0.01–0.12 | 0.12 ± 0.39 |
Monocyte count (G/L) | 0.05–0.3 | 1.27 ± 3.6 |
Lymphocyte count (G/L) | 1.2–3 | 11.48 ± 34.87 |
SNP | Gene | Test Model | Controls (n = 144) | Cases (n = 147) | p-Value |
---|---|---|---|---|---|
rs2114496205 | A20 | TT | 144 (100%) | 144 (97.96%) | |
TC | 0 (0%) | 3 (2.04%) | 0.497 | ||
p.K337Q | A20 | AA | 144 (100%) | 140 (95.24%) | |
AC | 0 (0%) | 7 (4.76%) | 0.059 | ||
p.P348L | A20 | TT | 144 (100%) | 137 (93.2%) | |
TC | 0 (0%) | 10 (6.8%) | 0.014 * | ||
rs374987145 | A20 | GG | 129 (89.58%) | 136 (92.52%) | |
GT | 15 (10.42%) | 11 (7.48%) | 0.613 | ||
rs214496684 | A20 | CC | 133 (92.36%) | 143 (97.28%) | |
CT | 11 (7.64%) | 4 (2.72%) | 0.121 | ||
rs751096907 | A20 | GG | 144 (100%) | 144 (97.96%) | |
GT | 0 (0%) | 3 (2.04%) | 0.497 | ||
c.1239-437 | Cezanne | TT | 144 (100%) | 142 (96.6%) | |
TA | 0 (0%) | 5 (3.4%) | 0.246 | ||
rs587631702 | Cezanne | TT | 141 (97.92%) | 144 (97.96%) | |
TA | 3 (2.08%) | 3 (2.04%) | 1 | ||
rs1230581026 | Cezanne | GG | 142 (98.61%) | 123 (83.67%) | |
GA | 2 (1.39%) | 24 (16.33%) | <0.001 *** | ||
p.E747K | CYLD | GG | 91 (63.2%) | 125 (85.03%) | |
GA | 53 (36.8%) | 22 (14.97%) | 0.001 ** | ||
c.2242+53 | CYLD | GG | 55 (38.19%) | 39 (26.53%) | |
GA | 89 (61.81%) | 108 (73.47% | 0.131 | ||
c.2242+121 | CYLD | GG | 105 (72.92%) | 113 (76.87%) | |
GA | 39 (27.08%) | 34 (23.13%) | 0.514 | ||
c.2242+169 | CYLD | GG | 85 (59.03%) | 115 (78.23%) | |
GA | 59 (40.94%) | 32 (21.77%) | 0.006 ** | ||
c.2242+188 | CYLD | GG | 99 (68.75%) | 117 (79.59%) | |
GA | 45 (31.25%) | 30 (20.41%) | 0.104 |
Gene/SNP | Type of Variant | Allele | MAF | HWE (p-Value) | |||
---|---|---|---|---|---|---|---|
ALL Patients | Controls | Controls | ALL Patients | All Population | |||
A20/rs2114496205 | Missense | T/C | 0.010 | 0.000 | N/A | 0.9006 | 0.9296 |
A20/p.K337Q | Missense | A/C | 0.024 | 0.000 | N/A | 0.7675 | 0.8355 |
A20/p.P348L | Missense | T/C | 0.034 | 0.000 | N/A | 0.6694 | 0.7656 |
A20/rs374987145 | Missense | G/T | 0.037 | 0.052 | 0.5097 | 0.6374 | 0.4251 |
A20/rs2114496684 | Stop-gained | C/T | 0.014 | 0.038 | 0.6337 | 0.8671 | 0.5721 |
A20/rs751096907 | Stop-gained | G/T | 0.010 | 0.000 | N/A | 0.9006 | 0.9296 |
Cezanne/c.1239-437 | Intron | T/A | 0.017 | 0.000 | N/A | 0.8339 | 0.8824 |
Cezanne/rs587631702 | Intron | T/A | 0.010 | 0.010 | 0.8993 | 0.9006 | 0.8589 |
Cezanne/rs1230581026 | Intron | GA | 0.082 | 0.007 | 0.9333 | 0.2812 | 0.4251 |
CYLD/p.E747K | Missense | GA | 0.075 | 0.184 | 0.006802 | 0.3268 | 0.01162 |
CYLD/c.2242+53 | Intron | GA | 0.367 | 0.309 | 0.000 | 0.000 | 0.000 |
CYLD/c.2242+121 | Intron | GA | 0.116 | 0.135 | 0.06017 | 0.1129 | 0.01442 |
CYLD/c.2242+169 | Intron | GA | 0.109 | 0.205 | 0.00199 | 0.1386 | 0.001569 |
CYLD/c.2242+188 | Intron | GA | 0.102 | 0.156 | 0.02627 | 0.1683 | 0.01162 |
A20 Expression | Cezanne Expression | |||||
---|---|---|---|---|---|---|
Characteristics | Low (n = 119) | High (n = 28) | p Value | Low (n = 132) | High (n = 15) | p Value |
Age (years) | 31.69 ± 20.7 | 28.34 ± 23.65 | 0.476 | 31.35 ± 21.12 | 29.92 ± 25.01 | 0.825 |
Sex. male (n. %) | 75 (63) | 15 (53.6) | 0.384 | 80 (60.6) | 8 (53.33) | 0.484 |
Urea (mmol/L) | 6.1 ± 3.52 | 6.85 ± 4.4 | 0.405 | 6.21 ± 3.7 | 7.55 ± 2.47 | 0.266 |
Glucose (mmol/L) | 7.92 ± 9.12 | 6.21 ± 2.6 | 0.407 | 7.09 ± 7.67 | 6.96 ± 3.39 | 0.958 |
Creatinine (µmol/L) | 91.09 ± 62.5 | 90.15 ± 64.2 | 0.951 | 87.04 ± 48.34 | 83.6 ± 38.44 | 0.827 |
Uric acid (µmol/L) | 470.45 ± 203.1 | 451.8 ± 256.2 | 0.725 | 463.1 ± 193.2 | 562.9 ± 335.5 | 0.146 |
Total bilirubin (µmol/L) | 14.83 ± 15.94 | 28.72 ± 58.07 | 0.044 * | 17.8 ± 28.9 | 15.76 ± 10.45 | 0.825 |
Direct bilirunbin (µmol/L) | 4.43 ± 9.97 | 14.6 ± 44.4 | 0.042 * | 6.38 ± 21.1 | 3.9 ± 4.21 | 0.712 |
Indirect bilirubin (µmol/L) | 11.14 ± 8.5 | 14.1 ± 14.4 | 0.218 | 11.44 ± 8.68 | 11.86 ± 7.08 | 0.882 |
Total protein (g/L) | 72.07 ± 7.43 | 112.5 ± 175.45 | 0.025 * | 79.14 ± 74.25 | 71.8 ± 6.68 | 0.756 |
Albumin (g/L) | 38.58 ± 4.9 | 37.46 ± 6.12 | 0.383 | 38.43 ± 5.17 | 39.85 ± 5.09 | 0.407 |
Globulin (g/L) | 33.4 ± 6 | 35.42 ± 9.98 | 0.242 | 33.67 ± 6.91 | 31.95 ± 6.03 | 0.447 |
Ferritin (µg/L) | 1008.3 ± 728.1 | 1127.8 ± 987.5 | 0.532 | 1085.1 ± 765.6 | 1026 ± 1038.9 | 0.812 |
AST (GOT) (U/L) | 60.46 ± 68.04 | 71.35 ± 62.6 | 0.51 | 61.16 ± 65.7 | 112.3 ± 81 | 0.022 * |
ALT (GPT) (U/L) | 43.19 ± 43.3 | 46.65 ± 40.8 | 0.743 | 46.14 ± 46.5 | 60.7 ± 39.66 | 0.339 |
GGT (UI/L) | 134.04 ± 143 | 150.94 ± 147.5 | 0.727 | 135.8 ± 142.7 | 196.5 ± 59.3 | 0.469 |
LDH (IU/L) | 2895.8 ± 4426.7 | 2813.2 ± 3693.9 | 0.938 | 2733.7 ± 4174.8 | 5706.3 ± 5921.4 | 0.039 * |
Erythrocyte count (T/L) | 4.2 ± 9.08 | 3.34 ± 0.95 | 0.675 | 4.05 ± 8.52 | 3.47 ± 0.75 | 0.828 |
Hemoglobin (g/L) | 92.54 ± 25.3 | 92.8 ± 20.7 | 0.966 | 92.08 ± 23.43 | 97 ± 18.06 | 0.519 |
Hematocrit (%) | 28.5 ± 7.54 | 28.7 ± 6.85 | 0.928 | 28.28 ± 7.2 | 29.47 ± 5.86 | 0.613 |
Nucleated erythrocyte count (G/L) | 0.23 ± 0.54 | 0.13 ± 0.18 | 0.416 | 0.21 ± 0.49 | 0.1 ± 0.12 | 0.508 |
Reticulocytes (%) | 1.44 ± 1.05 | 1.46 ± 1.42 | 0.859 | 1.52 ± 1.27 | 1.63 ± 1.68 | 0.824 |
Platelet count (G/L) | 102.2 ± 110.35 | 47.92 ± 52.6 | 0.034 * | 97.98 ± 92.5 | 40.1 ± 20.6 | 0.045 * |
WBC count (G/L) | 70.63 ± 104.7 | 94.87 ± 138.4 | 0.373 | 67.6 ± 100.7 | 74.1 ± 121.5 | 0.849 |
BM blasts (%) | 72.57 ± 26.53 | 64.72 ± 36.01 | 0.279 | 70.31 ± 28.89 | 65.69 ± 37.74 | 0.653 |
Neutrophil count (G/L) | 6.27 ± 20.07 | 6.73 ± 16.01 | 0.923 | 5.78 ± 18.8 | 3.76 ± 4.59 | 0.737 |
Eosinophil count (G/L) | 0.29 ± 0.97 | 0.11 ± 0.25 | 0.406 | 0.27 ± 0.91 | 0.05 ± 0.11 | 0.456 |
Basophil count (G/L) | 0.15 ± 0.48 | 0.07 ± 0.16 | 0.427 | 0.13 ± 0.44 | 0.005 ± 0.01 | 0.368 |
Monocyte count (G/L) | 1.51 ± 4.28 | 0.67 ± 1.04 | 0.385 | 1.42 ± 4.05 | 0.87 ± 1.18 | 0.668 |
Lymphocyte count (G/L) | 12.55 ± 16.2 | 21.88 ± 15.6 | 0.055 | 13.31 ± 39.9 | 21.36 ± 54.7 | 0.554 |
PLR | 50.78 ± 84.75 | 15.93 ± 22.47 | 0.046 * | 45.04 ± 78.14 | 20.62 ± 29.88 | 0.329 |
Relative expression of A20/GAPDH | 2.22 ± 2.53 | 2850.8 ± 13945.2 | 0.035 * | 18.97 ± 59.5 | 7222.9 ± 22486.6 | <0.001 *** |
Relative expression of CYLD/GAPDH | 1.92 ± 7.02 | 126.7 ± 494.5 | 0.009 ** | 2.87 ± 10.1 | 322.6 ± 780.9 | <0.001 *** |
Relative expression of Cezanne/GAPDH | 0.09 ± 0.2 | 14.82 ± 54.5 | 0.007 ** | 0.22 ± 1.61 | 57.2 ± 109.01 | <0.001 *** |
SNP | Gene | Test Model | A20 Expression | Cezanne Expression | ||||
---|---|---|---|---|---|---|---|---|
Low (n = 119) | High (n = 28) | p Value | Low (n = 132) | High (n = 15) | p Value | |||
rs2114496205 | A20 | TT | 116 (97.48%) | 28 (100%) | 129 (97.73%) | 15 (100%) | ||
TC | 3 (2.52%) | 0 (0%) | 0.246 | 3 (2.27%) | 0 (0%) | 0.497 | ||
p.K337Q | A20 | AA | 112 (94.42%) | 28 (100%) | 125 (94.7%) | 15 (100%) | ||
AC | 7 (5.88%) | 0 (0%) | 0.029 * | 7 (5.3%) | 0 (0%) | 0.059 | ||
p.P348L | A20 | TT | 109 (91.6%) | 28 (100%) | 122 (92.42%) | 15 (100%) | ||
TC | 10 (8.4%) | 0 (0%) | 0.007 ** | 10 (7.58%) | 0 (0%) | 0.007 ** | ||
rs374987145 | A20 | GG | 108 (90.76%) | 28 (100%) | 121 (91.67%) | 15 (100%) | ||
GT | 11 (9.24%) | 0 (0%) | 0.003 ** | 11 (8.33%) | 0 (0%) | 0.007 ** | ||
rs214496684 | A20 | CC | 115 (96.64%) | 28 (100%) | 128 (96.97%) | 15 (100%) | ||
CT | 4 (3.36%) | 0 (0%) | 0.246 | 4 (3.03%) | 0 (0%) | 0.246 | ||
rs751096907 | A20 | GG | 116 (97.48%) | 28 (100%) | 129 (97.73%) | 15 (100%) | ||
GT | 3 (2.52%) | 0 (0%) | 0.246 | 3 (2.27%) | 0 (0%) | 0.497 | ||
c.1239-437 | Cezanne | TT | 114 (95.8%) | 28 (100%) | 127 (96.21%) | 15 (100%) | ||
TA | 5 (4.2%) | 0 (0%) | 0.121 | 5 (3.79%) | 0 (0%) | 0.121 | ||
rs587631702 | Cezanne | TT | 117 (98.32%) | 27 (96.43%) | 129 (97.73%) | 15 (100%) | ||
TA | 2 (1.68%) | 1 (3.57%) | 0.683 | 3 (2.27%) | 0 (0%) | 0.497 | ||
rs1230581026 | Cezanne | GG | 97 (81.5%) | 28 (92.86%) | 109 (82.58%) | 14 (93.33%) | ||
GA | 22 (18.5%) | 2 (7.14%) | 0.019 * | 23 (17.42%) | 1 (6.67%) | 0.048 * |
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© 2025 by the authors. Published by MDPI on behalf of the Lithuanian University of Health Sciences. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
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Ha, L.T.; Giang, N.H.; Toan, N.L.; Giang, N.V.; Mao, C.V.; Nhat, N.Q.; Quan, T.D.; Hoang, N.H.; Hang, N.T.; Xuan, N.T. Cross-Sectional Study: Associations of A20 and Cezanne with Leukocyte Accumulation in B-Cell Acute Lymphoblastic Leukemia. Medicina 2025, 61, 1166. https://doi.org/10.3390/medicina61071166
Ha LT, Giang NH, Toan NL, Giang NV, Mao CV, Nhat NQ, Quan TD, Hoang NH, Hang NT, Xuan NT. Cross-Sectional Study: Associations of A20 and Cezanne with Leukocyte Accumulation in B-Cell Acute Lymphoblastic Leukemia. Medicina. 2025; 61(7):1166. https://doi.org/10.3390/medicina61071166
Chicago/Turabian StyleHa, Le Thuy, Nguyen Hoang Giang, Nguyen Linh Toan, Nguyen Van Giang, Can Van Mao, Nguyen Quoc Nhat, Tran Dang Quan, Nguyen Huy Hoang, Ngo Thu Hang, and Nguyen Thi Xuan. 2025. "Cross-Sectional Study: Associations of A20 and Cezanne with Leukocyte Accumulation in B-Cell Acute Lymphoblastic Leukemia" Medicina 61, no. 7: 1166. https://doi.org/10.3390/medicina61071166
APA StyleHa, L. T., Giang, N. H., Toan, N. L., Giang, N. V., Mao, C. V., Nhat, N. Q., Quan, T. D., Hoang, N. H., Hang, N. T., & Xuan, N. T. (2025). Cross-Sectional Study: Associations of A20 and Cezanne with Leukocyte Accumulation in B-Cell Acute Lymphoblastic Leukemia. Medicina, 61(7), 1166. https://doi.org/10.3390/medicina61071166