Differences in telomerase expression by the CD1a⁺ cells in Langerhans cell histiocytosis reflect the diverse clinical presentation of the disease

Abstract

Langerhans cell histiocytosis (LCH) is a disease characterized by an uncontrolled clonal proliferation of Langerhans cells, whose aetiology is still unclear. The clonal nature of LCH could support the hypothesis that it is a neoplastic disease with unlimited growth potential. One requirement for unlimited proliferation is the maintenance of telomere length. In a group of 70 patients, we set out to investigate whether a telomere maintenance mechanism is indeed active in LCH cells. This work showed that LCH cells from all restricted skin LCH lesions (6/6) expressed telomerase as assessed by human telomere reverse transcriptase (hTERT) immunohistochemistry, whereas LCH cells from the majority of the bone lesions analysed did not express hTERT (26/34). Interestingly, in contrast to the solitary bone lesions, LCH cells from lesions of multi-system patients always expressed telomerase (11/11), regardless of the lesional site. In situ telomeric repeat amplification protocol (TRAP) assays performed on different lesional sites showed that this telomerase was active. In addition, the telomere length of LCH cells from a hTERT-positive skin multi-system lesion was long and homogeneous when compared to that in the LCH cells from hTERT-negative bone single-system LCH lesions, which was heterogeneous in length. No evidence for an alternative lengthening of telomeres mechanism was found in hTERT-negative lesions. The difference in telomerase expression and telomere length at the different lesional sites and in biopsies from patients with solitary versus multi-system disease appears to reflect the diverse clinical presentation and course of this disease. The results from this study have important implications for understanding the nature of this disease.

Telomere length shortening in Langerhans cell histiocytosis

“…Meeker and A.M. De Marzo unpublished observations; Wu et al , 2006). For example, da Costa et al (2007) performed a study on telomerase expression in samples from patients with single system and multisystem LCH. They found that telomerase was expressed in the LC in 6/6 restricted skin lesions, 3/5 restricted lymph node lesions, 8/34 restricted bone lesions and 11/11 multisystem lesions (da Costa et al , 2007).…”

“…For example, da Costa et al (2007) performed a study on telomerase expression in samples from patients with single system and multisystem LCH. They found that telomerase was expressed in the LC in 6/6 restricted skin lesions, 3/5 restricted lymph node lesions, 8/34 restricted bone lesions and 11/11 multisystem lesions (da Costa et al , 2007). However, a complicating factor in interpreting these results is that the antibody that was utilized has been reported to detect nucleolin and not hTERT or hTERT‐related proteins (Wu et al , 2006).…”

Cell-Specific Gene Expression in Langerhans Cell Histiocytosis Lesions Reveals a Distinct Profile Compared with Epidermal Langerhans Cells

“…BCL2L1 (48,49), CASP3 (48), CASP8 (50), CCL2 (10), CCL20/MIP-3α (51), CD44 (52), CCL22 (10,53,54), CCR6 (51), CCR7 (55), CD11b/ITGAM (25,52,56–58), CD11c/ITGAX (25,38,52,57), CD14 (39), CD1a (Reviewed in 3,4,10), CD2 (25,52,58,59), CD36 (60), CD40 (39,61), CD49d/ITGA4 (25), CD54/ICAM1 (25,52), CD58 (25,52), CD68 (57), CD80 (39), CD83 (39,62), CD86 (39), cdc2a/p16 (49), CD-SIGN/CD209 (63), CFLAR (50), CLA/SELPLG (64), c-myc (65), CXCL11/I-TAC (51), CXCL8/IL-8 (10), DC-LAMP/CD208 (39), E-cadherin/CDH1 (25,26), FADD (50), FAS (66), Fascin/FSCN1 (67,68), FASLG (66), FLT3LG (38), GMCSF/CSF2 (10,69,70), GM-CSFR/CSF2RA (70), H-ras (65), hTERT (71,72), IFNγ (10,23,24), IL-10 (10,32,39), IL-17A (22), IL1R1 (73), IL-1α (10,23,24), IL-1β (10,23,24), IL-2 (10,24), IL-22 (22), IL2Rα/CD25 (58,74,75), IL-3 (10,24), IL-4 (10,23,24), IL-6 (10), Ki67 (…”

Langerhans cell histiocytosis: fascinating dynamics of the dendritic cell–macrophage lineage

“…Notably, reappearance of telomerase activity in somatic tissue is associated with the development of malignancy. While all LCH cells in skin lesions express the critical enzyme telomerase, as assessed by human telomere reverse transcriptase (hTERT) immunohistochemistry, most LCH cells from restricted bone lesions do not express telomerase (64). In contrast, in case of multi‐system involvement, the cells expressed the protein regardless of anatomic location.…”