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.
Front Med. 2022 Jun;16(3):403-415. doi: 10.1007/s11684-021-0858-1. Epub 2021 Jul 31.
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.
骨髓增殖性肿瘤（MPN）的发病率和死亡率主要由动脉和静脉并发症、向骨髓纤维化进展以及向急性白血病转化引起。然而，确定 MPN 患者风险分层的基于分子的生物标志物仍然是一个挑战。我们之前已经表明，干扰素调节因子-8（IRF8）和 IRF4 在髓系细胞中起肿瘤抑制作用。在这项研究中，我们评估了 MPN 患者中 IRF4 和 IRF8 的表达以及 JAK2V617F 突变等位基因负担。IRF4 表达降低的患者与骨髓纤维化（MF）和由 MPN 转化而来的继发性急性髓系白血病（sAML）中的 MPN 表型更为发达相关，而与原发性血小板增多症（ET）相比。ET 患者中 JAK2V617F 等位基因负担与 IRF8（P < 0.05）和 IRF4（P < 0.001）表达呈负相关，白细胞计数（WBC）与 IRF4 表达呈负相关（P < 0.05）。在真性红细胞增多症患者中，IRF8 表达与 JAK2V617F 等位基因负担呈负相关（P < 0.05）。羟基脲（HU）治疗 12 个月后，ET 患者分别观察到完全缓解（CR）、部分缓解（PR）和无反应（NR）分别为 67.5%、10%和 22.5%。在 3 个月时，CR 组患者的 IRF4 和 IRF8 表达高于 PR 和 NR 组患者。在 12 个月的治疗期间，低 IRF4 和 IRF8 表达与 HU 反应不良和高白细胞计数独立相关。我们的数据表明，IRF4 和 IRF8 的表达与 MPN 表型相关，这可能作为 ET 对 HU 反应的生物标志物。
