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Front. Med.    2022, Vol. 16 Issue (3) : 403-415    https://doi.org/10.1007/s11684-021-0858-1
RESEARCH ARTICLE
IRF4 and IRF8 expression are associated with clinical phenotype and clinico-hematological response to hydroxyurea in essential thrombocythemia
Xiao Huang, Tingting Ma, Yongmei Zhu, Bo Jiao, Shanhe Yu, Kankan Wang(), Jian-Qing Mi(), Ruibao Ren()
Shanghai Institute of Hematology, State Key Laboratory for Medical Genomics, Collaborative Innovation Center of Hematology, National Research Center for translational Medicine (Shanghai), Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
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Abstract

The morbidity and mortality of myeloproliferative neoplasms (MPNs) are primarily caused by arterial and venous complications, progression to myelofibrosis, and transformation to acute leukemia. However, identifying molecular-based biomarkers for risk stratification of patients with MPNs remains a challenge. We have previously shown that interferon regulatory factor-8 (IRF8) and IRF4 serve as tumor suppressors in myeloid cells. In this study, we evaluated the expression of IRF4 and IRF8 and the JAK2V617F mutant allele burden in patients with MPNs. Patients with decreased IRF4 expression were correlated with a more developed MPN phenotype in myelofibrosis (MF) and secondary AML (sAML) transformed from MPNs versus essential thrombocythemia (ET). Negative correlations between the JAK2V617F allele burden and the expression of IRF8 (P <0.05) and IRF4 (P<0.001) and between white blood cell (WBC) count and IRF4 expression (P <0.05) were found in ET patients. IRF8 expression was negatively correlated with the JAK2V617F allele burden (P <0.05) in polycythemia vera patients. Complete response (CR), partial response (PR), and no response (NR) were observed in 67.5%, 10%, and 22.5% of ET patients treated with hydroxyurea (HU), respectively, in 12 months. At 3 months, patients in the CR group showed high IRF4 and IRF8 expression compared with patients in the PR and NR groups. In the 12-month therapy period, low IRF4 and IRF8 expression were independently associated with the unfavorable response to HU and high WBC count. Our data indicate that the expression of IRF4 and IRF8 was associated with the MPN phenotype, which may serve as biomarkers for the response to HU in ET.
Keywords myeloproliferative neoplasms      IRF4      IRF8      hydroxyurea      essential thrombocythemia     
Corresponding Author(s): Kankan Wang,Jian-Qing Mi,Ruibao Ren   
Just Accepted Date: 12 July 2021   Online First Date: 02 August 2021    Issue Date: 18 July 2022
 Cite this article:   
Xiao Huang,Tingting Ma,Yongmei Zhu, et al. IRF4 and IRF8 expression are associated with clinical phenotype and clinico-hematological response to hydroxyurea in essential thrombocythemia[J]. Front. Med., 2022, 16(3): 403-415.
 URL:  
https://academic.hep.com.cn/fmd/EN/10.1007/s11684-021-0858-1
https://academic.hep.com.cn/fmd/EN/Y2022/V16/I3/403
ET (A) PV (B) PMF (C) sAML (D) P (A) ?vs. (B) P (A) ?vs. (C) P (A) ?vs. (D) P (B) ?vs. (C) P (B) ?vs. (D) P (C) ?vs. (D)
No. of patients ?(male:female) 40 (27:13) 13 (4:9) 5 (1:4) 5 (3:2) 0.026 0.06 1 1 0.326 0.524
Age ?(year) 55.5 ?(25–84) 57 ?(47–71) 62 ?(48–68) 58 ?(51–80) 0.315 0.233 0.107 0.64 0.394 0.748
WBC ?(× 109/L) 10.72 ?(5.2–39) 12.2 ?(7.39–21.48) 5.05 ?(0.82–18.52) 26 ?(17.33–55.8) 0.86 0.336 <0.001 0.331 <0.001 <0.001
Hb (g/L) 145.5 ?(54–170) 188 ?(160–207) 81 ?(50–123) 118 ?(74–152) <0.001 <0.001 <0.001 <0.001 <0.001 0.128
Hematocrit ?(%) 45.45 ?(27.0–49.1) 60 ?(48.2–70.8) 37.3 ?(18.7–61.7) 25.5 ?(22.9–46.9) <0.001 0.394 0.137 <0.001 <0.001 0.375
Erythrocyte ?count ?(× 109/L) 5.02 ?(2.18–5.79) 6.93 ?(5.78–9.91) 2.99 ?(1.80–4.65) 2.52 ?(2.20–5.65) <0.001 0.001 0.179 <0.001 <0.001 0.765
PLT (× 109/L) 956 (634–?2070) 660 ?(146–1167) 248 ?(29–2609) 231 ?(146–272) 0.006 0.055 <0.001 0.977 0.048 0.102
JAK2V617F ?allele? burden (%) 40.8 ?(12–97) 58.7 ?(40–97) 52.4 ?(35–77) 70.4 ?(21–98) 0.124 0.832 0.137 0.453 0.683 0.335
IRF8 expression ?(copies 105 ?IRF8/β-actin) 69.82 ?(15.28–121.29) 68.21 ?(46.26–98.81) 51.89 ?(43.75–80.31) 42.62 ?(32.28–111.84) 0.784 0.29 0.531 0.42 0.697 0.698
IRF4 expression ?(copies 106 ?IRF4/β-actin) 176.04 ?(33.84–465.1) 111.6 ?(51.06–268) 55.51 ?(21.38–84.88) 34.06 ?(29.35–74.65) 0.207 0.022 0.008 0.165 0.101 0.91
Tab.1  Laboratory and clinical characteristics of MPNs and sAML with JAK2V617F mutation at diagnosis
Fig.1  JAK2V617F allele burden (A) and IRF4 (B) and IRF8 (C) expression in the 63 patients enlisted in the study. Boxes represent the interquartile range that contains 50% of the subjects; the horizontal line inside marks the median, and the bars show the upper and lower ranges of values.
Factors n (%) IRF8 expression (copies ?105 IRF8/β-actin) P value IRF4 expression (copies ?106 IRF4/β-actin) P value
Age
?<60 years 32 (60.38%) 71.96 0.557 193.21 0.002
?≥60 years 21 (39.62%) 67.99 108.59
Gender
?Male 31 (58.49%) 71.85 0.599 150.71 0.445
?Female 22 (41.51%) 68.32 172.31
Diagnosis
?ET 40 (75.47%) 70.94 0.769 168.69 0.255
?PV 13 (24.53%) 68.68 131.97
WBC count
?<15 × 109/L 39 (73.58%) 74.36 0.041 171.66 0.148
?≥15 × 109/L 14 (26.42%) 59.32 126.32
JAK2V617F allele burden (%)
?<50% 30 (56.60%) 78.04 0.006 214.06 <0.001
?≥50% 23 (43.40%) 60.40 88.75
Tab.2  Baseline characteristic of the study group and comparison of IRF4 and IRF8 expression depending on clinical factors
Fig.2  Correlation of IRF4 and IRF8 expression with JAK2V617F allele burden and WBC count in ET (A–E) and PV (F–H) patients. The significant P values and r value for correlations are shown in the figure.
Fig.3  Rate of responses to HU according to the ELN criteria at 3 and 12 months in ET patients.
Fig.4  Clinical characteristics and IRF4 and IRF8 expression in the CR, PR, and NR groups evaluated at 3 months in ET patients. (A) Age; (B) JAK2V617F allele burden; (C) WBC count; (D) IRF4 expression; (E) IRF8 expression. *P<0.05, **P<0.01, ***P<0.001.
Fig.5  Receiver operating characteristic (ROC) curve analyses to explore the cut-off expression level of IRF4 and IRF8 in the cohort of ET patients: (A) IRF4 expression; (B) IRF8 expression. Note: The cut-off level for expression was determined using CR as a binary end point within 12 months. AUC, area under the curve.
Fig.6  Probability of achieving a complete clinico-hematological response (CR) to HU in 40 ET patients according to WBC count and IRF4 and IRF8 expression at baseline (A–C).
Factor No. CR (%) Univariate???? Multivariate????
P value Hazard ratio (95% CI) P value Hazard ratio (95% CI)
Age
?<60 years (21/25) 84% 0.006 2.1 (1.10–3.99) 0.717
?≥60 years (6/15) 40%
Sex
?Male (19/27) 70.4% 0.722 1.14 (0.70–1.88) 0.599
?Female (8/13) 61.5%
Splenomegaly
?No (25/37) 67.6% 1 1.01 (0.44–2.33) 0.325
?Yes (2/3) 66.7%
Thrombotic event
?No (23/35) 65.7% 1 0.82 (0.50–1.35) 0.851
?Yes (4/5) 80%
Hb level
?≥120 g/L (25/35) 71.4% 0.307 1.79 (0.60–5.33) 0.457
?<120 g/L (2/5) 40%
WBC count
?<15 × 109/L (25/30) 83.3% 0.001 4.17 (1.19–14.54) 0.021 8.14 (1.38–48.05)
?≥15 × 109/L (2/10) 20%
Platelet count
?<1000 × 109/L (18/23) 78.3% 0.171 1.48 (0.90–2.43) 0.657
?≥1000 × 109/L (9/17) 52.9%
JAK2V617F allele burden ?(%)
?<50% (25/26) 96.2% <0.001 6.73 (1.86–24.3) 0.223
?≥50% (2/14) 14.3%
IRF8 expression (copies 105 IRF8/β-actin)
?≥71.83 (15/16) 93.8% 0.004 1.88 (1.23–2.85) 0.030 2.51 (1.10–5.77)
?<71.83 (12/24) 50%
IRF4 expression (copies 106 IRF4/β-actin)
?≥107.11 (25/25) 100% <0.001 7.5 (2.06–27.3) 0.001 22.18 (3.65–134.77)
?<107.11 (2/15) 13.3%
Tab.3  Analysis of factors associated with the clinico-hematological response to HU in 40 patients with ET
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[1] FMD-21012-OF-RRB_suppl_1 Download
[1] LIU Hongxing, TONG Chunrong, CAI Peng, GU Jiangying, LIN Yuehui, TENG Wen, WANG He, ZHANG Ying, ZHU Ping. Observation of a higher JAK2 V617F homozygous mutated clone in polycythemia vera compared to essential thrombocythemia[J]. Front. Med., 2008, 2(3): 309-313.
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