Expression of enhancer of zeste homolog 2 (EZH2) protein in histiocytic and dendritic cell neoplasms with evidence for p-ERK1/2-related, but not MYC- or p-STAT3-related cell signaling

Abstract

EZH2 is an important enzymatic subunit of the epigenetic regulator polycomb repressive complex 2 (PRC2), which controls gene silencing through post-translational modification, and is overexpressed in various carcinomas and hematopoietic neoplasms. We found that the majority of cases of histiocytic and dendritic cell neoplasms, including histiocytic sarcoma, follicular dendritic cell sarcoma, Langerhans cell histiocytosis, and interdigitating dendritic cell sarcoma, show strong EZH2 expression by immunohistochemical staining, in contrast to benign histiocytic lesions and normal cellular counterparts, which did not show EZH2 expression, suggesting that this molecule may function as an oncogenic protein in these neoplasms. We correlated EZH2 expression with that of p-ERK1/2, MYC, and p-STAT3, potential regulators of EZH2, and found that 60-80% of these cases showed strong p-ERK1/2 expression, and only a minority of cases showed positivity for MYC or p-STAT3 in neoplastic cells. In cases of follicular dendritic cell sarcoma, Langerhans cell histiocytosis, histiocytic sarcoma, and interdigitating dendritic cell sarcoma with strong EZH2 expression, 90%, 89%, 70%, and 100% of cases showed co-expression of p-ERK1/2 with EZH2, respectively, while only a small percentage of these cases showed MYC or p-STAT3 co-expression with EZH2 (≤30%). These findings suggest that the p-ERK1/2 signaling cascade, but not the p-STAT3 and MYC signaling cascades, may regulate EZH2 expression in histiocytic and dendritic cell neoplasms, and that EZH2 and the p-ERK1/2 signaling cascade could serve as therapeutic targets for the treatment of these neoplasms. Interestingly, only a minority of cases of blastic plasmacytoid dendritic cell neoplasm exhibited high EZH2 expression, and only a minority of these cases showed p-ERK1/2 co-expression, suggesting that alternative mechanisms may contribute to tumorigenesis in this aggressive neoplasm.

Histiocytic cell neoplasms involving the bone marrow: summary of the workshop cases submitted to the 18th Meeting of the European Association for Haematopathology (EAHP) organized by the European Bone Marrow Working Group, Basel 2016

“…The importance of the integration of clinical (e.g., a syndromic context) and radiologic features (e.g., osteolysis, “hairy kidney”; see later) in the diagnosis cannot be overemphasized. The diagnostic value of the aberrant expression of various mutant or phosphorylated proteins, such as V600E mutant BRAF [ 4 ], phosphorylated extracellular signal-regulated kinases ( ERK1 /2) [ 5 ], or, as recently suggested, the enzymatic subunit of the polycomb repressive complex 2 ( EZH2 ) [ 6 ], still requires validation, but seems promising.…”

Cyclin D1 expression and novel mutational findings in Rosai‐Dorfman disease

“…The identification of recurrent mutations in the mitogen‐activated protein kinase (MAPK) pathway represents an advance in our understanding and therapy of histiocytic neoplasms (Classen et al , ; Haroun et al , ; Ozkaya et al , ; Tian et al , ; Tran et al , ). For example, many Langerhans cell histiocytosis (LCH) cases harbour mutations in either BRAF or other MAPK pathway genes, which introduced the option of targeted therapy (Badalian‐Very et al , ; Brown et al , ).…”

A case of Langerhans cell sarcoma on the scalp: Whole‐exome sequencing reveals a role of ultraviolet in the pathogenesis

“…As well as the typical histological features, because IHC showed the tumor to be strongly positive for EZH2 (Fig. S1c), whose expression is known to be highly correlated with the phosphorylation of ERK in histiocytic and dendritic cell neoplasms, 20 we speculate that the present case might also have been driven by the MAPK pathway through unknown mechanisms. However, other pathways may play a key role in the pathogenesis, as has been reported for some LCH cases 15 …”