IRF4 expression is low in Philadelphia negative myeloproliferative neoplasms and is associated with a worse prognosis

Abstract

Interferon regulatory factor 4 (IRF4) is involved in the pathogenesis of various hematologic malignancies. Its expression has been related to the negative regulation of myeloid-derived suppressor cells (MDSCs) and the polarization of anti-inflammatory M2 macrophages, thereby altering immunosurveillance and inflammatory mechanisms. An abnormal inflammatory status in the bone marrow microenvironment of myeloproliferative neoplasms (MPNs) has recently been demonstrated; moreover, in chronic myeloid leukemia a downregulated expression of IRF4 has been found. In this context, we evaluated the IRF4 expression in 119 newly diagnosed consecutive Philadelphia negative MPNs (Ph- MPNs), showing a low expression among the MPNs phenotypes with a more significant decrease in primary myelofibrosis patients. Lower IRF4 levels were associated with JAK2 + and triple negatives cases carrying the worst prognosis. Furthermore, the IRF4 levels were related to leukemic transformation and a shorter leukemia-free survival; moreover, the risk of myelofibrosis transformation in polycythemia vera and essential thrombocythemia patients was more frequent in cases with lower IRF4 levels. Overall, our study demonstrates an IRF4 dysregulated expression in MPNs patients and its association with a worse prognosis. Further studies could validate these data, to improve our knowledge of the MPNs pathogenesis and confirm the IRF4 role as a new prognostic factor.

Keywords: IRF4 expression; Philadelphia negative MPNs; Prognosis.

Fig. 1

IRF4 expression in Ph-MPNs. A Comparison of IRF4 expression between healthy controls and MPN groups. The IRF4 expression was statistically significantly lower in every MPNs category than in healthy controls. B IRF4 expression according to the gene driver mutation in MPNs. A lower IRF4 expression was more frequently concomitant with JAK2 + and triple-negative status than with the CALR gene mutation MPN group. C The MPN patients group with leukemic transformation showed a lower IRF4 expression than the group without leukemic evolution. Boxplots representing the distribution. The box always extends from the 25th to 75th percentiles. The line in the box represents the median. The whiskers go down to the smallest value and up to the largest

Fig. 2

IRF4 prognostic impact in Ph-MPNs. A LFS analysis in all MPN patients included in this study according to the IRF4 expression value. B LFS analysis in MF patients according to the IRF4 expression value. C LFS analysis in PMF patients according to the IRF4 expression value. D OS analysis in MF patients according to the IRF4 expression value. E OS analysis in PMF patients according to the IRF4 expression value. F Probability analysis of evolution to post-PV and post-ET MF according to the IRF4 expression value. The cut off of the IRF4 expression (0.022) was calculated by ROC analysis