Abstract 2362: Identification and characterization of pathogenetic pathways and potential therapeutic targets in tumors derived from histiocytes and follicular dendritic cells
Authors: Piccaluga Pier-Paolo , Rossi Maura , Motta Giovanna , Hartmann Sylvia , Doering Claudia , Fuligni Fabio , Agostinelli Claudio , Sapienza Maria Rosaria , Laginestra Maria Antonella , Melle Federica , Etebari Maryam , Navari Mohsen , Gazzola Anna , Mannu Claudia , Bertuzzi Clara , Tripodo Claudio , Hansmann Martin L. , Facchetti Fabio , Pileri Stefano A 
Published: May 2015

Tumors derived from histiocytes and follicular dendritic cells (FDC) are extremely rare, constituting less than 1% of hematopoietic tumors. Among others, follicular dendritic cell sarcoma (FDC-S), histiocytic sarcoma (HS) , and Langerhans histiocytosis (LH) are the commonest types. The clinical course is variable from indolent to aggressive; however, the disease is more often incurable. Further, probably due to their rarity and complexity, the pathobiology of these tumor is nearly unknown at present, with only scattered studies being reported.

In this study, we investigated by gene expression profiling (GEP) and extensive immunohistochemistry (IHC) a relatively large series of cases, aiming 1) to identify and characterize functional pathways possibly involved in the pathogenesis of the disease, and 2) to unveil potential targets for novel treatments.

We studied by GEP FDC-S (N=30), LH (N=9), and HS (N=4) as well as non neoplastic cells including tissue microdissected FDC (N=5), CD1c+ myeloid dendritic cells (N=4), peripheral blood monocytes (N=8), and human cultured fibroblasts (N=3). All cases were studied with the Illumina DASL whole genome microarray. The same cases as well as and independent cohort was then used for IHC validation studies.

First, unsupervised approaches (principal component analysis and hierarchical clustering) indicated that tissue samples were distinct from cellular ones, while the different entities could not be clearly separated. Second, we found by supervised comparison (ANOVA, p&lt;0.05, fold change ≥2, FDR according to Benjamini-Hockeberg), the 3 tumor types could be discriminated. Particularly, the tumors differed for genes related to immune response (consistent with their histogenesis) and to intracellular signaling. In this regard, we found several oncogenic pathways to be differentially activated while others were consistently deregulated including those related to cellular adhesion, chemotaxis, angiogenesis and response to growth factors.

We then compared each tumor type with the specific supposed counterpart (i.e. FDC-s vs. FDC; LH vs. myeloid DC; HS vs. monocytes) and identified genes and cellular programs deregulated in each of them. Interestingly, all tumors presented with consistent deregulation of previously unknown potential therapeutic targets, including PDGF/PDGFRs, PTEN, JAK/STAT, mTOR/AKT, and EGFR. Importantly, IHC confirmed GEP data and confirmed the activation of these selected pathways.

We defined for the first time the cellular programs deregulated in tumors derived from histiocytes and FDC and identified remarkable potential therapeutic targets. As appropriate experimental models (i.e. cell lines, animal models) are not available at present, international collaboration would be advisable to confirm these observation in large series before eventually moving to early phase clinical trials.

Citation Format: Pier-Paolo Piccaluga, Maura Rossi, Giovanna Motta, Sylvia Hartmann, Claudia Doering, Fabio Fuligni, Claudio Agostinelli, Maria Rosaria Sapienza, Maria Antonella Laginestra, Federica Melle, Maryam Etebari, Mohsen Navari, Anna Gazzola, Claudia Mannu, Clara Bertuzzi, Claudio Tripodo, Martin L. Hansmann, Fabio Facchetti, Stefano A Pileri. Identification and characterization of pathogenetic pathways and potential therapeutic targets in tumors derived from histiocytes and follicular dendritic cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2362. doi:10.1158/1538-7445.AM2014-2362