IRF4 and IRF8 expression are associated with clinical phenotype and clinico-hematological response to hydroxyurea in essential thrombocythemia

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

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Acknowledgements

This work was supported by the National Key Research and Development Program (No. 2016YFC0902800 to Ruibao Ren), the Key Project of National Natural Science Foundation of China (No. 81530006 to Ruibao Ren), Shanghai Collaborative Innovation Program on Regenerative Medicine and Stem Cell Research (No. 2019CXJQ01 to Ruibao Ren), National Natural Science Foundation of China (No. 81870112 to Ruibao Ren).

Compliance with ethics guidelines

Xiao Huang, Tingting Ma, Yongmei Zhu, Bo Jiao, Shanhe Yu, Kankan Wang, Jian-Qing Mi, and Ruibao Ren declare that they have no conflict of interest. This manuscript does not involve a research protocol requiring approval by the relevant institutional review board or ethics committee. All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2000 (5). Informed consent was obtained from all patients or guardians of patients for being included in the study.

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