SPIB, a novel immunohistochemical marker for human blastic plasmacytoid dendritic cell neoplasms: characterization of its expression in major hematolymphoid neoplasms

Abstract

Key Points• SPIB is an Ets transcription factor involved in plasmacytoid dendritic cell differentiation.• SPIB protein expression can be used as a marker for human blastic plasmacytoid dendritic cell neoplasms.SPIB is an Ets transcription factor that is expressed exclusively in mature B cells, T-cell progenitors, and plasmacytoid dendritic cells. In the present study, we developed a novel mAb against the SPIB protein and characterized its expression in major hematolymphoid neoplasms, including a series of 45 cases of blastic plasmacytoid dendritic cell (BPDC) neoplasms and their potential cutaneous mimics. We found that SPIB is expressed heterogeneously among B-and T-cell lymphoma types. Interestingly, SPIB is expressed in a large proportion of nongerminal center type DLBCLs. In cutaneous neoplasms, SPIB is overexpressed in all BPDC neoplasms, but none of its cutaneous mimics. SPIB remains overexpressed in all cases that lack 1 or 2 of the markers used for BPDC neoplasms (ie, CD4, CD56, TCL1, and CD123). We conclude that SPIB expression can be used as a tool for diagnosing BPDC neoplasms, but it needs to be tested in conjunction with the growing arsenal of markers for human plasmacytoid dendritic cells. (Blood. 2013;121(4):643-647) IntroductionSPIB is an Ets family transcription factor that is expressed exclusively in mature B cells, T-cell progenitors, and plasmacytoid dendritic cells. 1-3 SPIB is required for full BCR signaling and T cell-dependent Ab responses. 4 SPIB is central to the germinal center (GC) reaction because those in SPIB-deficient mice are smaller, persist for less time after immunization, and contain more apoptotic cells than those of wild-type animals. 4 During B-cell maturation, it is first induced in the pre-B-to immature B-cell transition, 5 overexpressed during the GC reaction, 3 and repressed by PRDM1/Blimp1 once plasmacytic differentiation has been initiated. 6 Interestingly, SPIB has also been shown to target Blimp1 directly, providing a regulatory loop essential for the maintenance of GC and memory B cells, thereby preventing the initiation of the plasma cell program of differentiation. 7 Under neoplastic conditions, the SPIB locus has been found to be affected by chromosomal imbalances comprising gains/ amplifications and translocations in activated B-cell (ABC)-type diffuse large B-cell lymphoma (DLBCL) cell lines and clinical samples. 8,9 In fact, SPIB is one of the components of the Wright algorithm that classifies DLBCLs into the GC and ABC types according to their expression profile. 10 In addition, knock-down of SPIB by RNAi is toxic to ABC DLBCL cell lines, but not to other DLBCL subtypes or myeloma, suggesting a role for this putative oncogene in the pathogenesis of ABC-type DLCBL. 8,11 Together with its role during B-cell differentiation, SPIB has been shown to be a key regulator of human plasmacytoid dendritic cell development 1,12 and a component of the signature of blastic plasmacytoid dendritic cell (BPDC) neoplasms, 13 which were formerly known as blastic natural kille...

BDCA-2 (CD303): a highly specific marker for normal and neoplastic plasmacytoid dendritic cells

“…Remarkably, the high level of performance of the clone 124B3.13 is unique among the large set of PDC markers commonly used for BPDCN diagnosis, such as CD123, TCL1, BCL11a, CD2AP, as well as SPIB. [1][2][3]9 Moreover, our findings complement previously published data obtained by flow cytometry using the AC144 clone, 10 that demonstrated that positivity for BDCA-2 has the highest diagnostic score within a panel of markers used for BPDCN identification and confirmed that BPDCN does not cross the boundary with other hematopoietic neoplasms.…”

The multifaceted biology of plasmacytoid dendritic cells

“…Furthermore, Spib −/− pDCs exhibit attenuated expression of pDC-specific genes and display defects in type I IFN production following TLR7 or TLR9 stimulation. SPIB was also recently shown to be a novel immunohistochemical marker for the identification of human blastic pDC neoplasms 56 .…”

Expression of CD31/PECAM-1 (Platelet Endothelial Cell Adhesion Molecule 1) by Blastic Plasmacytoid Dendritic Cell Neoplasms

“…Interpersonal and intrapersonal immunophenotypic variations, such as CD4/CD56 positivity followed by negativity for both markers in subsequent biopsy specimens from a single patient, have been reported. 5,7 These findings underscore the importance of adding new antigens to the known repertoire of proteins expressed by BPDCN because their assessment may aid in early recognition of this tumor or help explain its biology.…”

“…1-6 However, this profile overlaps substantially with those of other hematolymphoid malignant neoplasms, predominantly NK cell lymphoma and/or leukemia and myeloid leukemias with skin involvement. 2,4-7 Moreover, the immunophenotypic diversity of BPDCN is greater than previously recognized. 2,5,7 Although the exact proportion of aberrant phenotypes remains unknown, negativity of at least 1 of the 4 markers CD4, CD56, CD123, and TCL-1 was demonstrated in 34% to 36% of cases in 2 large studies, emphasizing the need to disclose additional immunophenotypic features of this lethal neoplasm.…”

“…2,5,7 Although the exact proportion of aberrant phenotypes remains unknown, negativity of at least 1 of the 4 markers CD4, CD56, CD123, and TCL-1 was demonstrated in 34% to 36% of cases in 2 large studies, emphasizing the need to disclose additional immunophenotypic features of this lethal neoplasm. 5,7 …”