Gene expression analysis of dendritic/Langerhans cells and Langerhans cell histiocytosis

Abstract

Langerhans cell histiocytosis (LCH) is a neoplastic disorder that results in clonal proliferation of cells with a Langerhans cell (LC) phenotype. The pathogenesis of LCH is still poorly understood. In the present study, serial analysis of gene expression (SAGE) was applied to LCs generated from umbilical cord blood CD34+ progenitor cells to identify LC-specific genes and the expression of these genes in LCH was investigated. Besides the expression of several genes known to be highly expressed in LCs and LCH such as CD1a, LYZ, and CD207, high expression of genes not previously reported to be expressed in LCs, such as GSN, MMP12, CCL17, and CCL22, was also identified. Further analysis of these genes by quantitative RT-PCR revealed high expression of FSCN1 and GSN in all 12 LCH cases analysed; of CD207, MMP12, CCL22, and CD1a in the majority of these cases; and CCL17 in three of the 12 cases. Immunohistochemistry confirmed protein expression in the majority of cases. The expression of MMP12 was most abundant in multi-system LCH, which is the LCH type with the worst prognosis. This suggests that expression of MMP12 may play a role in the progression of LCH. These data reveal new insight into the pathology of LCH and provide new starting points for further investigation of this clonal proliferative disorder.

Notch is active in Langerhans cell histiocytosis and confers pathognomonic features on dendritic cells

“…In addition, LCH cells selectively displayed transcripts for matrix-degrading enzymes matrix metalloproteinase 1 (MMP1), MMP9, and MMP12, 22 which have already been described in LCH lesions using immunohistochemistry. 6,23 Analysis of LCH-specific genes also revealed potential autoand/or paracrine signaling loops. The TNF family member TRAIL was selectively detected in LCH cells (Table 2 and supplemental Figure 5), whereas high-level expression of functional receptors (TNFRSF10A and B) was shared with other DCs.…”

“…This process may be explained by the production of tissue-degrading enzymes, particularly MMPs that are expressed in LCH lesions. 6,23 Therefore, we investigated whether JAG2 might also be implicated in the pathogenesis of LCH lesions by MMP induction. MoDCs were stimulated with JAG2 and with TNF␣, which is a known strong inducer of MMPs as a control.…”

Histiocytic and Dendritic Cell Neoplasms

“…Genomic analysis of LCH have not yet shown a characteristic chromosomal abnormality, with CGH often showing losses on chromosomes 1p, 5, 6, 7, 9, 16, 17, and 22q, and gains on chromosomes 2q, 4q, and 12 [13]. A recent whole genome gene expression by the SAGE technique has identified several genes known to be highly expressed in Langerhans cells such as CD1A, LYZ, and CD207 (langerin), in addition to other genes not previously known to be expressed, such as GSN, MMP12, CCL17, and CCL2 [14].…”

New Insights Into the Molecular Pathogenesis of Langerhans Cell Histiocytosis

“…However, the highly specific targeting capacity found in vivo can provide the basis for future development of CR2113 for diagnostic imaging and/or treatment modality, thus fostering studies aimed at improving its antitumor activity by radiolabeling and/or by conjugation with immunotoxins or BRAF inhibitors. Finally, based on the high expression of metalloproteinase-12 in multisystem LCH and its putative role in the disease progression [122], concurrent studies investigating metalloproteinase inhibitors such as GM6001 are presently in progress [123].…”