IRF4 Expression in Blastic Plasmacytoid Dendritic Cell Neoplasms
Charles M van Slambrouck, Elizabeth Hyjek, Sandeep Gurbuxani. University of Chicago, Chicago, IL
Background: Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare neoplasm derived from precursors of type 1 interferon producing plasmacytoid dendritic cells (pDCs). Treatment outcome for these patients remains poor and design of appropriate therapy is hampered by an incomplete understanding of the oncogenic events involved in malignant transformation. IRF4 is a hematopoietic cell-restricted transcription factor. In malignancies such as plasma cell myeloma, the tumor cells are addicted to aberrant IRF4 expression and IRF4 inhibition has been shown to be toxic to malignant plasma cells. IRF4 expression can be downregulated by the immunomodulatory drug lenalidomide making it a candidate for targeted therapy in other IRF4 dependent tumors. Since IRF4 along with IRF8 directs dendritic cell subset development and functional diversity, we set to out to determine the frequency of IRF4 expression in reactive proliferations of pDCs and BPDCNs in primary clinical samples as a first step to determine the requirement for IRF4 BPDCN tumorigenesis.
Design: Archival paraffin embedded material was examined by immunohistochemistry. Staining was graded for intensity and localization. IRF4 expression was assessed in seven samples from five patients. Expression of IRF4 in non-BPDCN pDCs was assessed in two tonsils, one lymph node with Castleman's disease, and two bone marrows with nodular expansions of reactive pDCs secondary to either chronic myelomonocytic leukemia or a therapy-related myelodysplastic syndrome.
Results: IRF4 expression was observed in a small fraction of pDCs from all tissues with non-BPDCN pDCs. Expression of IRF4 in patients with BPDCN was as follows: three different samples from two individual patients had strong, consistent expression of IRF4 with nuclear localization. Consistent, but weak IRF4 expression was observed in one bone marrow. Weak and focal IRF4 expression was seen in one bone marrow.